α-phosphonosulfonate squalene synthetase inhibitors and method

ABSTRACT

α-Phosphonosulfonate compounds are provided which inhibit the enzyme squalene synthetase and thereby inhibit cholesterol biosynthesis. These compounds have the formula ##STR1## wherein R 2  is OR 5  or R 5a  ; R 3  and R 5  are independently H, alkyl, arylalkyl, aryl or cycloalkyl; R 5a  is H, alkyl, arylalkyl or aryl; R 4  is H, alkyl, aryl, arylalkyl, or cycloalkyl;, Z is H, halogen, lower alkyl or lower alkenyl; and R 1  is a lipophilic group which contains at least 7 carbons and is alkyl, alkenyl, alkynyl, mixed alkenyl-alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl; as further defined above; including pharmaceutically acceptable salts and or prodrug esters of the phosphonic (phosphinic) and/or sulfonic acids.

REFERENCE TO OTHER APPLICATIONS

This is a division of application Ser. No. 266,843, filed Jul. 5, 1994,now U.S. Pat. No. 5,470,845 which is a division of application Ser. No.109,762, filed Aug. 20, 1993, now abandoned, which is acontinuation-in-part of application Ser. No. 967,904, filed Oct. 28,1992, now abandoned.

FIELD OF THE INVENTION

The present invention relates to new α-phosphonosulfonate compoundswhich are useful in inhibiting cholesterol biosynthesis by inhibiting denovo squalene production, to hypocholesterolemic and antiatheroscleroticcompositions containing such compounds and to a method of using suchcompounds for inhibiting cholesterol biosynthesis and atherosclerosis.

BACKGROUND OF THE INVENTION

Squalene synthetase is a microsomal enzyme which catalyzes the reductivedimerization of two molecules of farnesyl pyrophosphate (FPP) in thepresence of nicotinamide adenine dinucleotide phosphate (reduced form)(NADPH) to form squalene (Poulter, C. D.; Rilling, H. C., in"Biosynthesis of Isoprenoid Compounds", Vol. I, Chapter 8, pp. 413-441,J. Wiley and Sons, 1981, and references therein). This enzyme is thefirst committed step of the de novo cholesterol biosynthetic pathway.The selective inhibition of this step should allow the essentialpathways to isopentenyl tRNA, ubiquinone, and dolichol to proceedunimpeded. Squalene synthetase along with HMG-CoA reductase have beenshown to be down-regulated by receptor mediated LDL uptake (Faust, J.R.; Goldstein, J. L.; Brown, M. S. Proc. Nat. Acad. Sci. U.S.A. 1979,76, 5018-5022), lending credence to the proposal that, inhibitingsqualene synthetase will lead to an up-regulation of LDL receptorlevels, as has been demonstrated for HMG-CoA reductase, and thusultimately should be useful for the treatment and prevention ofhypercholesterolemia and atherosclerosis.

U.S. Pat. No. 3,657,282 (Merck) (Division U.S. Pat. No. 3,822,296)discloses antibiotics of the structure ##STR2## wherein R=SO₃ H, SO₂ R*,H, hydrocarbyl other than alkyl (eg. alkenyl, alkynyl, phenyl andnaphthyl), substituted hydrocarbyl, CO₂ H, CO₂ R*, SO₃ NR₂,heterocycle*, amino*, OH, OR, SH, SR, CHO, halogen NO₂, CN, PO₃ H₂, AsO₃H₂, acyl, --CHR¹ R³ where R¹ =H, Me; R³ =R as above, preferably at leastone R not =H, R preferably contains 1-10 carbons. *=optionallysubstituted.

Starting materials employed to prepare the above antibiotics include##STR3## wherein R can be SO₃ H, and X and Y are hydroxy or functionalequivalent precursor to epoxide: eg. OH, halo, azide, RCO₂ --, RSO₂ O--,R₂ S⁺ --, R₃ N⁺ --, ArO--, R₂ PO₂ --, RSO₂ NR¹ --. One of X and Y mustbe an oxygen radical.

EP 89/0-344-980 (Smith Kline) discloses α-antagonists of the structure##STR4## wherein Y or Z may be --SO₂ R, --P(R)O(OR), --PR₂ O, --PO(OR)₂,and amides.

WO 88/00061 (Amersham) discloses Technetium-99 complexes for bonescanning having the structure ##STR5## wherein R¹ and R³ =H, SO₃ H oralkyl substituted with SO₃ H and optionally one or more heteroatoms; R⁴can also be SO₃ H or OH, NH₂, NHMe, NMe₂, lower alkyl substituted with apolar group;

R² =same as R⁴ except not SO₃ H and n=0, 1.

U.S. Pat. No. 4,032,521 (Merck) discloses inter-mediates, incephalosporin synthesis, of the structures ##STR6##

WO 90/07513 (Gas Research Institute) discloses electrolytes for fuelcells of the structure ##STR7## wherein R=organic radicals with 1 ormore F atoms;

R¹ =H, alkali metal, Zn, Cd;

R² =H, lower alkyl;

r=2, 3; and x, y=1, 2, 3.

U.S. Pat. No. 4,254,215 (Ciba Geigy AG) discloses a process forphotographic developers wherein one component of a developer solutionis:

    HS--D--(W).sub.n

wherein

n=1 to 4.

D=optionally substituted, saturated or unsaturated aliphatic radical(<40 carbons), can be interrupted by heteroatoms such as O, SO₂, NH, NR.

W=PO₃ R₂, SO₃ R, SO₂ R, --NY--SO₃ R, --SO₂ NR₂, --SSO₃ R, CO₂ R, OH, NR₃⁺, NR₂, CONR₂.

DE 89/3739691-A (Hoechst) (Derwent #89-173507/24) discloses herbicidesand plant growth regulators of the structure ##STR8## wherein Y=CH, N;X=O, S; Z═CH, N;

R¹, R² =C1-C6 alkyl or alkoxy;

R³ =H, C1-C6 alkyl or alkoxy, C2-C6 alkenyl, alkynyl, alkenyloxy,alkynyloxy; all optionally substituted with one or more halogens; and

R⁴ =H, C1-C4 alkyl or physiologically acceptable cation.

New intermediates are disclosed of the structures ##STR9##

Burton, D. J., J. Am. Chem. Soc. 1989, 111, 1773-1776 discloseselectrolytes and chelators of the structures

    (HO).sub.2 P(O)CF.sub.2 SO.sub.3 Na (HO).sub.2 P(O)CF.sub.2 SO.sub.3 H

Su, D.; Cen. W.; Kirchmeier, R. L.; Shreeve, J. M., Can. J. Chem. 1989,67, 1795-1799, disclose electrolytes and chelators of the structures##STR10##

Farrington, G. K.; Kumar, A.; Wedler, F. C., J. Med. Chem. 1985, 28,1668-1673 discloses compound 10 as an inhibitor of aspartatetranscarbamylase. Compound 24 is a synthetic intermediate. ##STR11##

Musicki, B.; Widlanski, T. S. Tetrahedron Lett.1991, 32, 1267-1270discloses compound 4 as a synthetic intermediate. ##STR12##

Carretero, J. C.; Demillequand, M.; Ghosez, L., Tetrahedron 1987, 43,5125-5134 discloses ##STR13## for use in the synthesis of vinylphosphonates via a Horner-Emmons reaction.

Callahan, L.; Ng, K.; Geller, D. H.; Agarwal, K.; Schwartz, N. B.,Analytical Biochemistry 1989, 177, 67-71 discloses an analog of ADP(adenosine diphosphate) of the structure ##STR14##

DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is providedα-phosphonosulfonate compounds which inhibit cholesterol biosynthesis,and thus are useful as hypocholesterolemic and antiatheroscleroticagents and have the following structure I. ##STR15## wherein R² is OR⁵or R^(5a), R³ and R⁵ are the same or different and are H, alkyl,arylalkyl, aryl, cycloalkyl, a metal ion or other pharmaceuticallyacceptable cations as defined below, or a prodrug ester;

R^(5a) is H, alkyl, arylalkyl or aryl;

R⁴ is H, alkyl, cycloalkyl, aryl, arylalkyl, metal ion or otherpharmaceutically acceptable cations as defined below, or a prodrugester;

Z is H, halogen, lower alkyl or lower alkenyl;

R¹ a lipophilic group containing at least 7 carbons and is alkylcontaining 7 to 25 carbons in the chain; alkenyl containing from 7 to 25carbon atoms in the chain and from 1 to 6 double bonds; alkynylcontaining 1 to 6 triple bonds; mixed alkenyl-alkynyl containing 1 to 5double bonds and 1 to 5 triple bonds; and where in the above groupsalkenyl and/or alkynyl may be substituted or unsubstituted; cycloalkyl;cycloheteroalkyl linked through a carbon on the ring or a heteroatom;aryl; heteroaryl; heteroarylalkyl; cycloalkylalkyl;cycloheteroalkylalkyl; or a group of the structure ##STR16## wherein Aris aryl (such as phenyl or naphthyl), heteroaryl (5 or 6 membered) andmay include one to three additional rings fused to Ar (such as aryl,cycloalkyl, heteroaryl or cycloheteroalkyl) and wherein (CH₂)_(p)contains from 1 to 15 carbons, preferably 2 to 12 carbons, in the chainand may include 0, 1, 2 or 3 double bonds and/or 0, 1, 2 or 3 triplebonds in the normal chain, and may contain an ether or amino function inthe chain, and/or may include 0, 1, 2 or 3 substituents as defined belowfor R⁶ ; and R⁶, R⁷, R⁸ and R^(8a) are the same or different and are H,alkyl containing 1 to 40 carbons, preferably from 3 to 25 carbons,alkoxy containing 1 to 40 carbons, preferably from 3 to 25 carbons,alkenyl containing 2 to 40 carbons, preferably from 3 to 25 carbons,alkenyloxy containing 2 to 40 carbons, preferably from 3 to 25 carbons,alkynyl containing 2 to 40 carbons, preferably from 3 to 25 carbons,alkynyloxy containing 2 to 40 carbons, preferably from 3 to 25 carbons,cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, cycloalkyl,cycloalkylalkyl, Ar-alkyl, (such as arylalkyl), ArO (such as aryloxy),Ar-amino (such as arylamino), hydroxy, halogen, nitro, Ar (such asaryl), amino, substituted amino wherein the amino includes 1 or 2substituents (which are alkyl, alkenyl, aryl or any of the Ar groupsmentioned above), thiol, alkylthio, Ar-thio (such as arylthio),alkylsulfinyl, Ar-sulfinyl (such as arylsulfinyl), alkylsulfonyl,Ar-sulfonyl (such as arylsulfonyl), carboxy, cyano, alkoxycarbonyl,aminocarbonyl, alkylcarbonyloxy, Ar-carbonyloxy (such asarylcarbonyloxy), Ar-carbonylamino (such as arylcarbonylamino) oralkylcarbonylamino, as well as any of the Ar groups as defined above,and preferably wherein the total number of carbons in the substitutedAr--(CH₂)_(p) -- group exceeds 10 carbons; including pharmaceuticallyacceptable salts thereof such as alkali metal salts such as lithium,sodium or potassium, alkaline earth metal salts such as calcium ormagnesium, as well as zinc or aluminum and other FDA approved cationssuch as ammonium, choline, diethanolamine, ethylenediamine, and salts ofnaturally occuring amino acids such as arginine, lysine, alanine and thelike.

The (CH₂)_(p) group may contain 1, 2, 3 or more alkyl, alkoxy, alkenyl,alkynyl, hydroxy and/or halogen substituents as well as any of thesubstituents defined for R⁶.

Thus, the compounds of the invention include the following sub-genuses:##STR17##

The term "prodrug esters" as employed herein includes prodrug esterswhich are known in the art for both phosphorus and carboxylic acids.Examples include the following groups: (1-alkanoyloxy)alkyl such as,##STR18## wherein R¹⁸, R¹⁹ and R²⁰ are H, alkyl, aryl or arylalkyl;however R¹⁸ O cannot be HO. Examples of such prodrug esters include CH₃CO₂ CH₂ --, ##STR19##

Other examples of suitable prodrug esters include ##STR20## wherein R¹⁸can be H, alkyl (such as methyl or t-butyl), arylalkyl (such as benzyl)or aryl (such as phenyl); R²¹ is H, alkyl, halogen or alkoxy, R²² isalkyl, aryl, arylalkyl or alkoxyl, and n₁ is 0, 1 or 2; or R³ and R⁵ canbe linked together as in ##STR21##

Unless otherwise indicated, the term "lower alkyl" or "alkyl" asemployed herein alone or as part of another group includes both straightand branched chain hydrocarbons, containing 1 to 40 carbons, preferably1 to 20 carbons, in the normal chain, more preferably 1 to 12 carbons,such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl,pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like as well as such groupsincluding 1 to 4 substituents such as F, Br, Cl or I or CF₃, alkoxy,aryl, arylalkyl, alkenyl, cycloalkyl, amino, hydroxy, alkylamido,alkanoylamino, arylcarbonylamino, nitro, cyano, thiol and/or alkylthio,as well as any of the other substituents as defined for R⁶.

Unless otherwise indicated, the term "cycloalkyl" as employed hereinalone or as part of another group includes saturated or partiallyunsaturated cyclic hydrocarbon groups containing 3 to 12 carbons,preferably 3 to 8 carbons, which include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl andcyclododecyl, cyclohexenyl, any of which groups may be substituted with1 to 4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, arylcarbonylamino,amino, nitro, cyano, thiol and/or alkylthio, as well as any of the othersubstituents as defined for R⁶.

Unless otherwise indicated, the term "aryl" as employed herein refers tomonocyclic or bicyclic aromatic groups containing from 6 to 10 carbonsin the ring portion, such as phenyl, naphthyl, or phenyl or naphthylsubstituted with 1 to 4 substituents such as alkyl, halogen (Cl, Br orF), alkoxy, hydroxy, amino, alkanoylamino, arylcarbonylamino, aryl,arylalkyl, cycloalkyl, alkylamido, nitro, cyano, thiol and/or alkylthio,as well as any of the other substituents as defined for R⁶.

The term "aralkyl", "aryl-alkyl" or "aryl-lower alkyl" as used hereinalone or as part of another group refers to alkyl groups as discussedabove having an aryl substituent, such as benzyl or phenethyl, ornaphthylpropyl.

The term "lower alkoxy", "alkoxy", "aryloxy" or "aralkoxy" as employedherein alone or as part of another group includes any of the abovealkyl, aralkyl or aryl groups linked to an oxygen atom.

The term "lower alkylthio", "alkylthio", "arylthio" or "aralkylthio" asemployed herein, alone or as part of another group includes any of theabove alkyl, alkyl, aralkyl or aryl groups linked to a sulfur atom.

The term "lower alkylamino", "alkylamino", "arylamino", or"arylalkylamino" as employed herein alone or as part of another groupincludes any of the above alkyl, aryl or arylalkyl groups linked to anitrogen atom.

The term "alkanoyl" as used herein alone or as part of another grouprefers to alkyl linked to a carbonyl group.

Unless otherwise indicated, the term "lower alkenyl" or "alkenyl" asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 40 carbons, preferably 3 to 30 carbonsin the normal chain, which include one to six double bonds in the normalchain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl,3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl,3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl,4,8,12-tetradecatrienyl, and the like, and which may be optionallysubstituted with 1 to 4 substituents, namely, halogen, alkyl, alkoxy,alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxy,alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol and/oralkylthio, as well as any of the other substituents as defined for R⁶.

Unless otherwise indicated, the term "lower alkynyl" or "alkynyl" asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 40 carbons, preferably 2 to 20 carbonsin the normal chain, which include one triple bond in the normal chain,such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl,2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl,3-nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl and the like, and whichmay be optionally substituted with 1 to 4 substituents, namely, halogen,alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino,hydroxy, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano,thiol, and/or alkylthio, as well as any of the other substituents asdefined for R⁶.

Examples of suitable (CH₂)_(p) groups include ##STR22##

The term "halogen" or "halo" as used herein refers to chlorine, bromine,fluorine, and iodine as well as CF₃, with chlorine or fluorine beingpreferred.

The term "amino" as used herein refers to unsubstituted amino as well asmonosubstituted amino or disubstituted amino wherein the substituentsmay be alkyl and/or aryl.

The term "metal ion" refers to alkali metal ions such as sodium,potassium or lithium and alkaline earth metal ions such as magnesium andcalcium, as well as zinc and aluminum.

The term "cycloheteroalkyl" as used herein as an R¹ substituent refersto a 5-, 6- or 7-membered saturated ring which includes 1 to 2 heteroatoms such as nitrogen, oxygen and/or sulfur, linked to the carbon "C"of ##STR23## through a carbon atom or a heteroatom, where possible,optionally via the linker (CH₂)_(p) (which is defined above), such as##STR24## and the like. The above groups may include 1 to 3 substituentssuch as any of the R⁶ groups as defined above. In addition, any of theabove rings can be fused to a cycloalkyl, aryl, heteroaryl orcycloheteroalkyl ring.

The term "heteroaryl⃡ as an R¹ substituent refers to a 5- or 6- memberedaromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen,oxygen or sulfur, which is linked to the carbon "C" of ##STR25## througha carbon atom or a heteroatom, where possible, optionally via the linker(CH₂)_(p) (which is defined above), such as ##STR26## and the like. Theabove groups may include 1 to 3 substituents such as any of the R⁶groups as defined above. In addition, any of the above rings can befused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

The term cycloheteroalkylalkyl" as defined by R¹ refers tocycloheteroalkyl groups as defined above linked through a C atom orheteroatom to the "C" of ##STR27## group through a (CH₂)_(p) chainwherein p is preferably 1 to 8.

The term "heteroarylalkyl" as defined by R¹ refers to a heteroaryl groupas defined above linked through a C atom or heteroatom to the ##STR28##through a --(CH₂)_(p) -- chain as defined above, where p is preferably 1to 8.

Preferred are compounds of formula I and IA wherein R² is OR⁵ and R⁵ isa metal ion such as Na or K, or H or a pharmaceutically acceptable saltor more preferably a prodrug ester;

R³ is H, a metal ion such as Na or K;

R⁴ is a metal ion such as Na or K;

R¹ is alkenyl such as ##STR29## wherein (CH₂)_(x) is defined as(CH₂)_(p) above and x is preferably 2 to 8, ##STR30## 20 m is 1 to 5;##STR31## n=1 to 15; R¹¹, R^(11a), R^(11b), and R^(11c) areindependently selected from H, alkyl such as propyl, alkoxy, such asmethoxy or propyloxy, alkenyl such as ##STR32## wherein R¹², R^(12a) andR^(12b) are independently selected from H, aryl (such as phenyl ornaphthyl), alkylphenyl (such as p-propylphenyl, p-pentylphenyl), alkylcontaining 1 to 20 carbons (such as p-heptyl), halo, alkoxy (such asmethoxy or propyloxy), alkenyl (such as ##STR33## arylalkyloxy (such asphenethyloxy), alkenyloxy (such as ##STR34## aryloxy (such as phenoxy),phenylalkyl (such as benzyl, phenylpropyl), alkylphenoxy (such asorthobutylphenoxy), alkenylphenyl (such as ##STR35## wherein R¹⁴ isaryl, heteroaryl, aryloxy, heteroaryloxy, cycloalkyl, heterocycloalkyl,and (CH₂)_(p') and (CH₂)_(p") are as defined above for --(CH₂)_(p) --.Preferred p' and p" are independently 1 to 4;

    Ar.sup.1 --O--Ar.sup.2 --(CH.sub.2).sub.p --

wherein Ar¹ and Ar² are independently selected from any of the Ar groupsdefined hereinbefore, and (CH₂)_(p) is as defined hereinbefore.

The compounds of the invention may be prepared according to thefollowing reaction sequences. ##STR36##

    __________________________________________________________________________    Scheme IXA                                                                    Alkylation Reaction Methodology                                                                           product IK                                        __________________________________________________________________________    A.        A.                                                                              1) ≧1 eq. of base                                                                              R.sup.5a ≠ Aryl                                 2) R.sup.5a -Hal (Hal = I or Br)                                              VIB                                                               B.        B.                                                                              1) Chlortrimethylsilane (TMSCl)                                                                       R.sup.5a ≠ Aryl                                 Et.sub.3 N                                                                    2) R.sup.5a -Hal                                                              VIB                                                               C.                                                                              or      C.                                                                              1) base                 R.sup.5a = R.sup.7 CHOH                               2) aldehyde             R.sup.7 = aryl, alkyl or H                            1) TMSCl, (C.sub.2 H.sub.5).sub.3 N                                           2) aldehyde                                                       D.        D.                                                                              1) base                 R.sup.5a = aryl                                       2) aryl halide, Pd[P(C.sub.6 H.sub.5).sub.3 ].sub.4 or                        Ni[P(C.sub.6 H.sub.5).sub.3 ].sub.4                               __________________________________________________________________________     ##STR37##

Referring to "General Reaction" Scheme I, compounds of the invention ICmay be prepared by alkylating the phosphonosulfonate II by reacting IIwith compound III in the presence of an appropriate base and an inertorganic solvent under an inert atmosphere to form IC, followed bydeprotection to the various acid forms ID, IE, IF and IG.

In carrying out the above reaction, the phosphonosulfonate II isemployed in a molar ratio to compound III of within the range of fromabout 5:1 to about 0.8:1, and preferably from about 3:1 to about 1.2:1.The reaction is carried out under an inert atmosphere, such as argon,initially preferably at a reduced temperature of within the range offrom about -78° to about 80° C., and more preferably from about 0° toabout 50° C., although the reaction may be completed at roomtemperature.

Examples of inert organic solvents suitable for use herein include, butare not limited to dimethylformamide (DMF), tetrahydrofuran (THF),dimethylsulfoxide (DMSO), hexamethylphosphoramide (HMPA) or diethylether (Et₂ O), or mixtures thereof.

Examples of bases suitable for use in carrying out the above reactioninclude, but are not limited to, alkali metal hydrides, such as sodiumhydride (which is preferred), potassium hydride, lithium-, sodium- orpotassium bis(trimethylsilyl)amide, lithium diisopropylamide orbutyllithium.

Referring to Scheme IA, starting compounds of formula IIC wherein R₁ ²,R₁ ³, and R₁ ⁴ of II as defined in Scheme I may be prepared by reactingstarting sulfonate IIA with a strong base such as any of those used inScheme I, in the presence of or followed by chlorophosphate IIB, and aninert organic solvent such as used in Scheme I, to form IIC.

In carrying out the reaction of Scheme IA, chlorophosphate IIB will beemployed in a molar ratio to sulfonate IIA of within the range of fromabout 3:1 to about 1:2, and preferably from about 2.0:1 to about 1:1.The reaction is carried out at a temperature of within the range of fromabout -100° to about 30° C., and preferably from about -90° to about 0°C.

Referring to Scheme II, compounds of the invention IC may be prepared byalkylating the phosphonosulfonate IC' with an alkylhalide, ZX (IIIA) (Zis alkyl and X is as defined in Scheme I), or with a halogenating agentZX¹ (where Z is halogen except F and X¹ is succinimido, Cl, Br or I, orOH; when Z is F, ZX¹ is XeF₂), ##STR38##

The above reactions are carried out in the presence of appropriate inertorganic solvent as described above, under an inert atmosphere, to formIC.

In carrying out the above reaction, the phosphonosulfonate IC' isemployed in a molar ratio to compound IIIA or IIIA' of within the rangeof from about 2:1 to about 0.2:1, and preferably from about 1.5:1 toabout 0.7:1. The reaction is carried out under an inert atmosphere, suchas argon, initially preferably at a reduced temperature of within therange of from about -78° C. to about 80° C., and more preferably fromabout 0° C. to about 50° C., although the reaction may be completed atroom temperature. Bases and solvents appropriate for this reaction areas described for Scheme I.

Referring to Scheme III Part A, compounds of the invention IC may beprepared by alkylating the phosphonosulfonate II with compound III inthe presence of an appropriate base and an inert organic solvent (asdescribed hereinbefore with respect to Scheme I) preferablydimethylformamide (DMF), under an inert atmosphere to form IC.

In carrying out the above reaction, the phosphonosulfonate II isemployed in a molar ratio to compound III of within the range of fromabout 5:1 to about 0.8:1, and preferably from about 3:1 to about 1.5:1.The reaction is carried out under an inert atmosphere, such as argon,initially, preferably at a reduced temperature of within the range offrom about -78° to about 80° C., and more preferably from about 0° toabout 50° C., although the reaction may be completed at roomtemperature.

Referring to Schemes III Part B and III Part C, compounds of theinvention IC' may be prepared through the palladium catalyzed basepromoted coupling of allylic acetates (Types 1 or 2) with thephosphonosulfonate II to provide the coupled product of the inventionIC'. Either allylic isomer serves as a substrate in the reaction.

In carrying out the above reactions, the phosphonosulfonate II isemployed in a molar ratio to allylic acetate of within the range of fromabout 5:1 to about 0.8:1, and preferably from about 3:1 to about 1.5:1.The reaction is carried out under an inert atmosphere, such as argon,initially preferably at a reduced temperature of within the range offrom about -78° to about 110° C., and more preferably from about 0° toabout 80° C., although the reaction may be completed at roomtemperature.

The above reactions are carried out in the presence of a suitable inertorganic solvent as described hereinbefore with respect to Scheme I,preferably employing tetrahydrofuran (THF) or dimethylformamide (DMF).Suitable bases are sodium hydride and sodium bis(trimethylsilyl)amide,and preferably bis(trimethylsilyl)acetamide (BSA) in the presence ofpalladium (O) catalyst such as Pd[(C₆ H₅)₃ ]₄.

The base or BSA is employed in a molar ratio to allylic acetate withinthe range of from about 4:1 to about 1:1, while the Pd(O) is employed ina molar ratio to allylic acetate of within the range of from about0.005:1 to about 0.5:1.

Referring to Scheme IV, Part A, the coupling reaction is carried outwith (dialkoxyphosphinyl)methane sulfonate ethyl ester II to yield thesulfonate salt ID directly from the reaction. The product emerges bymeans of a concomitant iodide promoted dealkylation of the sulfonateester.

The Scheme IV Part A, reaction is carried out in a manner similar toScheme I.

The sulfonate salt ID may also be formed as shown in Scheme IV, PartB(1) and (2). Part B(1) depicts the dealkylation of the sulfonate esterICa to yield ID, using various reagents as shown in the reactionsequence set out hereinbefore, while B(2) shows the cleavage of an arylmethanesulfonate ester ICb by aqueous alkali containing from about 5 toabout 20% by weight base) and heating at a temperature within the rangeof from about 40° to about 100° C., to give ID.

Referring to Scheme V, the diacid salt IE is prepared by the furtherhydrolysis of monoacid ID employing aqueous alkali (containing fromabout 5° to about 20% by weight base) optionally in the presence of acosolvent, such as dimethoxyethane, dioxane or THF, and heating at atemperature within the range of from about 40° to about 100° C.

Referring to Scheme VI, the (dihydroxyphosphinyl)methanesulfonic acidmonoester IF is prepared by the cleavage of the phosphorous ester IC(wherein R₁ ² and R₁ ³ are each lower alkyl, arylalkyl, cycloalkyl andR₁ ⁴ is lower alkyl, arylalkyl, cycloalkyl or aryl) withbromotrimethylsilane (TMSBr), optionally in the presence of a protonscavenger such as 2,4,6-collidine, hexamethyl disilazane, alkyl,trimethylsilane, bis(trimethylsilyl)trifluoroacetamide, pyridine ortriethylamine, followed by aqueous alkali (as described above exceptthat elevated temperatures are not necessary) or water wherein the TMSBris employed in a molar ratio to IC of within the range of from about 2:1to about 15:1, preferably from about 2: to about 5:1.

Scheme VII Parts A, B and C sets out the chemical processes employed forthe deprotection of phosphonosulfonate triester IC to phosphonosulfonicacid IG.

In Scheme VII, Part A shows the direct deprotection of the ester ICthrough the agency of trimethylsilyl iodide (TMSI) (employs a molarratio of TMSI:IC of within the range of from about 3:1 to about 20:1,preferably from about 3.5:1 to about 5:1) optionally in the presence ofa proton scavenger as defined above, and followed by aqueous alkali (asdescribed above) or water at a temperature of within the range of fromabout 0° to about 50° C.

In Scheme VII Part B, phosphonosulfonic triacid IG is formed via a twostep process where in the first step, the sulfonate ester is removed asdescribed in Part B, Scheme IV and in the second step treatment withbromotrimethylsilane optionally in the presence of a proton scavenger asdefined above, yields the silyl esters which are then hydrolyzed viaaqueous alkali (as described hereinbefore) or water.

In Scheme VII Part C, the phosphonate esters are removed (from IC) firstwith bromotrimethylsilane (TMSBr) (employing a molar ratio of TMSBr:ICof within the range of from about 2:1 to about 20:1, preferably fromabout 2.5:1 to about 5:1) optionally in the presence of a protonscavenger as defined above, to provide the intermediatebis(silyl)esters. Subsequent cleavage of the sulfonate ester withpotassium iodide (18-crown-6, THF) and hydrolysis (MOH and H₂ O) yieldsthe phosphonosulfonic triacid IG.

Schemes VIII, IX, IXA and X relate to the preparation of α-(alkyl- oraryl-hydroxyphosphinyl)sulfonates.

Schemes VIII and IX depict the general chemical process for theformation of diesters IK, and their deprotection to form IL and IO,respectively.

Scheme IXA depicts the P-H route to diester IK. Starting sulfonate VI istreated with a strong base followed by dialkyl chlorophosphite(employing a molar ratio of dialkyl chlorophosphite:VI of within therange of from 1:1 to about 10:1), followed by hydrolysis with waterunder acidic conditions, to form alkoxyphosphinyl sulfonate IO whichserves as an intermediate for the synthesis of substituted (alkyl- oraryl-alkoxyphosphinyl)methylsulfonate diesters via alkylation of IO. Thealkylation methods are shown in Parts A, B, C and D.

In Scheme IXA Part A, diester IK where R^(5a) ≠ aryl is formed byselective alkylation of IO by treating IO with base such as NaH, KH,LDA, butyllithium, Li-, Na- or K-bis(trimethylsilyl)amide and a halideVIB of the structure

    VIB R.sup.5 Hal

wherein Hal is I or Br, as described with respect to Scheme I.

In Scheme IXA Part B, diester IN where R⁵ ≠ aryl is formed by treatmentof IO with chlorotrimethylsilane (TMSCl) and organic base such astriethylamine (Et₃ N) in the presence of alkylating agent VIB. Incarrying out this alkylation, the silane compound is employed in a molarratio to IO of within the range of from about 1:1 to about 5:1,preferably from about 1:1 to about 3:1 while VIB is employed in a molarratio to IO of within the range of from about 0.8:1 to about 10:1.

In Scheme IXA Part C, IK where R^(5a) is R⁷ CHOH (and R⁷ is H, aryl oralkyl) is prepared by treating IO with base followed by aldehyde R⁷ CHO,carried out by employing a molar ratio of R⁷ CHO to IO of from about 1:1to about 10:1. Alternatively, IO can be treated with (CH₃)₃ SiCl and anorganic base (such as triethylamine) followed by an aldehyde, followedsubsequently with a standard desilylation reaction (such astetrabutylammonium fluoride in THF) to provide IK with R⁵ =R⁷ CHOH.

In Scheme IXA, Part D IO is reacted with an aryl halide in the presenceof a base such as triethylamine and Pd[P(C₆ H₅)₃ ]₄, Ni[P(C₆ H₅)₃ ]₄ orother nickel and palladium catalysts, to yield IK when R^(5a) is aryl.

Scheme X depicts the preparation of (hydroxyphospinyl)methanesulfonicacid diester IN by alkylation of diester V by treatment of V with base,such as NaH, and alkylating agent III as described hereinbefore inScheme I. The intermediate V may be prepared via a coupling reaction ofthe alkylsulfonate VII with phosphonic acid chloride VIII employing amolar ratio of VII:VIII of within the range of from about 0.5:1 to about10:1, preferably from about 1.5:1 to about 3:1, similar to thatdescribed in Scheme IA, for the conversion of IIA to IIC.

Schemes XI and XIA depict various routes (A, B and C) for thedeprotection of diesters IK to yield IM.

Scheme XII Part A depicts the preparation of salts IQ by dealkylating IOusing techniques as described hereinbefore, preferably with KI andacetone, to form monoester IP and then subjecting IP to hydrolysis toform salt IQ.

In Scheme XII Part B, the ester IP is treated with aldehyde (R⁷ CHO) inthe presence of organic base such as triethylamine,diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene, to form IKwhere R^(5a) is R⁷ CHOH. In this reaction, the aldehyde is employed in amolar ratio to IP of within the range of from about 1:1 to about 10:1,preferably from about 1:1 to about 5:1.

Scheme XIII depicts an alternate route to IC where IIA is treated withbase (as per Scheme IA) and chlorophosphite (as described hereinbefore)and an oxidant such as m-chloroperbenzoic acid (MCPBA), t-C₄ H₉ COOH,hydrogen peroxide or I₂ /H₂ O to form IC.

Scheme XIV (Parts A and B) depict the preparation of prodrug esters.

Referring to Scheme XV, the individual isomers or enantiomers of theformula I compounds of the invention may be prepared, in accordance withthe present invention, by treating the (R,R)-diamine XXR (or(S,S)-diamine XXS) where R^(a) is alkyl or aralkyl, with an alkylphosphonic dihalide XXA, such as methylphosphonic dichloride, in thepresence of a tertiary amine base and an aprotic solvent such asbenzene, toluene, dichloromethane or diethyl ether, to form thealkylphosphondiamide XXI which is metalated with a base such asn-butyllithium, sec-butyllithium, t-butyllithium or lithiumdiisopropylamide, to form the lithium anion of XXI which is thenalkylated by treatment the halide R¹ X (IIIa) such as the iodide##STR39## in the presence of an inert organic solvent such astetrahydrofuran (THF), diethyl ether or dimethoxyethane or mixturesthereof, at a temperature within the range of from about -90° to about25° C., preferably from about -80° to about 0° C., to form XXII.Compound XXII is reacted with a base as above to form the lithium anionof XXII which is sulfurated with tetramethylthiuram disulfide or thecorresponding tetraethyl derivative at a temperature within the range offrom about -100° to about 0° C., preferably from about -90° to about-60° C., to form a mixture of isomers XXIIIR and XXIIIS (which are novelcompounds in accordance with the present invention).

Where the sulfuration is carried out at below about 0° C., preferably atabout -60° C. to about -100° C., and the starting diamine is the(R,R)-diamine XXR and Z is H, a mixture of major XXIIIS (α-(S)) andminor XXIIIR (α-(R)) thiocarbamate isomers (about 3:1 mixture at -90°C.) is obtained.

It should be noted that in the above and following discussions andschemes α-(R) and α-(S) refer to the enantiomeric configuration at thechiral carbon center adjacent to the phosphorus and sulfur moieties.

It will be appreciated that where the (S,S)-diamine XXS is employed inplace of (R,R)-diamine XXR and Z is H, the major isomer obtained will bethe α-(R)-isomer XXIIIR.

The thiocarbamate isomers XXIIIS and XXIIIR can be separated bychromatography on silica gel, crystallization or HPLC. The individualand separate diastereomers (XXIIIS and XXIIIR) are then separatelysubjected to acid hydrolysis (such as treatment with aqueous acid suchas HCl), to form compound XXIVR or XXIVS (which are novel compounds inaccordance with the present invention) which are separately subjected tooxidation (such as reaction with H₂ O₂ in the presence of formic acid,acetic acid or mixtures of formic and acetic acids) and salt formationby base treatment or ion exchange chromatography, to form the individualenantiomers IS and IR of the invention.

In carrying out the reactions of Scheme XV, the starting (R,R)-diaminewith R⁹ =methyl is prepared by a two-step reductive methylation of theL-(+)- tartaric acid salt (available from racmeic1,2-trans-cyclohexanediamine, Gasbol, F. et al (1972) Acta. Chem. Scand.26, 3605 and Onuma, K. et al, (1980) Bull. Chem. Soc. Jap. 53, 2012) asfollows: ##STR40##

Other examples of XXR and XXS where R⁹ is alkyl or aralkyl are preparedas reported in the prior art as follows: Alexakis, A. et al, J. Org.Chem., 1992, 57, 1224-1237; Denmark, S. et al, J. Org. Chem., 1991, 56,5063-5079; Hanessian, S. et al, Tetrahedron, 1992, 33, 7659-7662; andKoeller, K. J. et al, Tetrahedron Lett., 1991, 32, 6297-6300.

The (R,R)-diamine XXR (or XXS) is employed in a molar ratio to thealkylphosphonic dichloride XXA of within the range of from about 0.5:1to about 3:1, preferably from about 0.9:1 to about 1.5:1. The aminebase, such as triethylamine, pyridine, diisopropylethylamine will beemployed in a molar ratio to the alkylphosphonic dichloride XXIA ofwithin the range of from about 1:1 to about 5:1, preferably from 1.5:1to about 3:1.

The metalation (anion formation) of XXI is carried out at a temperaturewithin the range of from about -90° to about 0° C., preferably fromabout -80° to about -60° C., employing a molar ratio of base compound toalkylphosphondiamide XXI of within the range of from about 0.8:1 toabout 2:1, preferably from about 0.9:1 to about 1.3:1. The alkylatingagent R¹ X (III) where X is preferably iodide, but may be Cl or Br aswell, will be employed in a molar ratio to alkylphosphondiamide XXI ofwithin the range of from about 1:1 to about 4:1, preferably from about1:1 to about 2:1.

As seen in Scheme XVI Part A(1), compound XXII may be prepared by avariety of routes which will be apparent to those skilled in the art.

The metalation of XXII is carried out at a temperature within the rangeof from about -100° C. to about 0° C., preferably from about -60° C. toabout -80° C. employing a molar ratio of base to XXII of within therange of from about 2:1 to about 0.8:1, preferably from about 1.4:1 toabout 0.9:1.

The lithium anion of XXII is then sulfurated employing a molar ratio oftetramethylthiuram disulfide: lithium anion of XXII of within the rangeof from about 3:1 to about 1:1, preferably from about 2:1 to about 1:1.

The acid hydrolysis of the individual isomer XXIIIS and XXIIIR to thecorresponding thiocarbamate XXIVS and XXIVR, respectively, is carriedout by employing aqueous strong acid, such as aqueous HCl, formic acidor sulfuric acid, optionally in the presence of acetonitrile, dioxane orother inert organic solvent. The thiocarbamates XXIVS and XXIVR may beoxidized by conventional techniques, for example, by reaction withhydrogen peroxide in the presence of acetic acid or formic acid, ormixtures thereof or peracids such as peracetic in acetic acid ormetachloroperbenzoic acids in dichloromethane or diethyl ether, or usingOxone in alcoholic solvents, to the sulfonic acid which is treated withalkali metal hydroxide, such as KOH, NaOH, or LiOH or an ion exchangeresin to form the triacid salt, IS or IR.

Referring to Scheme XV Part B, in accordance with the present invention,in an alternate synthesis of the Part A method, alkylphosphondiamide XXI(or (S,S)-isomer) is metalated by reaction with a base as describedabove, such as n-butyllithium, sec-butyllithium, t-butyllithium orlithium diisopropylamide in the presence of an inert organic solventsuch as hexane, tetrahydrofuran or diethylether to form the lithiumanion of XXI which is sulfurated by treatment with sulfur and subjectedto thiocarbamoylation with a dialkyl thiocarbamoyl halide to form XXV (anovel compound in accordance with the present invention). Compound XXVis then metalated by treatment with a base as described above, alkylatedby treatment with R¹ Hal and the resulting mixture of isomers XXIIIS andXXIIIR are separated as described hereinbefore. Isomers XXIIIS andXXIIIR may then be subjected to acid hydrolysis and oxidation and saltformation as described with respect to XXIIIS and XXIIIR in Part A, toform IR and IS.

In carrying out the Scheme XV Part B method, the base, preferablyn-butyllithium, is reacted with alkylphosphondiamine XXI under an inertatmosphere such as argon or nitrogen at a temperature within the rangeof from about -100° to about 0° C., preferably from about -60° to about-80° C., employing a molar ratio of alkyllithium:XXI of within the rangeof from about 0.8:1 to about 2:1, preferably from about 1.2:1 to about1:1.

The sulfuration reaction of lithiated XXI (with sulfur) is carried outat a temperature within the range of from about -90° to about 0° C.,preferably from about -80° to about -40° C., employing a molar ratio ofsulfur:lithiated XXI of within the range of from about 4:1 to about 1:1,preferably from about 2:1 to about 1:1.

Thiocarbamoylaton of the sulfurated XXI with the dialkylthiocarbamoylhalide, preferably, dimethyl- or diethyl-thiocarbamoyl chloride iscarried out at a temperature within the range of from about -60° toabout 25° C., preferably from about -30° to about 0° C., employing amolar ratio of dialkylthiocarbomoyl halide:sulfurated XXI of within therange of from about 4:1 to about 1:1, preferably from about 2:1 to about1:1. The thiocarbamoylation reaction is optionally carried out in thepresence of a weak organic base, such as triethylamine or pyridine.

The thiocarbamoylated compound XXV is metalated with a base, asdescribed above, preferably n-butyllithium, at a temperature within therange of from about -90° to about -60° C., preferably from about -80° toabout -70° C., under an inert atmosphere such as argon or nitrogen,employing a molar ratio of alkyllithium: thiocarbamoylated compound XXVof within the range of from about 2:1 to about 0.8:1, preferably fromabout 1.4:1 to about 0.9:1.

Alkylation of the lithiated XXV is carried out at a temperature withinthe range of from about -90° to about 0° C., preferably from about -80°to about -40° C., employing a molar ratio of R¹ Hal:lithiated XXV ofwithin the range of from about 4:1 to about 0.8:1, preferably from about1.5:1 to about 0.9:1. The alkylation is preferably carried out in thepresence of a weak base such as hexamethylphosphoramide (HMPA), ortetramethylethylene diamine.

Still another alternative method for preparing the desired enantiomersof formula I compounds, in accordance with the present invention, isshown in Scheme XV Part C wherein starting (R,R)-diamine XXR (or thecorresponding (S,S-)-diamine XXS) is made to undergo a phosphorousdiamide formation by treating a solution of XXR and weak organic basesuch as triethylamine or pyridine, in an inert organic solvent such asTHF, dichloromethane or toluene, with phosphorus trichloride under aninert atmosphere such as argon or nitrogen, and then treating theresulting filtrate (chilled), under an inert atmosphere, such as argon,with water, and a tertiary amine base, to form the phosphorous diamideXXVII. The diamide XXVII may then be subjected to a condensationreaction with the aldehyde XXVIII

    R.sup.1 CHO

and a silylating agent such as, for example, bis(trimethylsilyl)acetamide, bis(trimethylsilyl) trifluoroacetamide or hexamethyldisilazane in the presence of an inert organic solvent, such asmethylene chloride, toluene or THF, under an inert atmosphere, such asargon or nitrogen, to form a mixture of protected isomers XXIXR(α-(R)isomer) and XXIXS (α-(S)isomer).

The isomers XXIXR and XXIXS are separated by chromatography or otherconventional means such as crystallization and each of the α-(R) isomerXXIXR and α-(S) isomer XXIXS in solution in an inert organic solventsuch as THF, diethyl ether, acetonitrile or dichloromethane, isseparately treated with a fluoride source such as tetrabutylammoniumfluoride, aqueous hydrofluoric acid or lithium tetrafluoroborate, toform the compounds XXXR and XXXS.

Each of the isomers XXXR and XXXS can then be separately made to undergoa Mitsunobu displacement (Rollin, P., Tetrahedron Lett. 1986, 27,4169-4170) wherein each of XXXR and XXXS is separately treated withdimethyl (or diethyl) dithiocarbamic acid, zinc salt, andtriphenylphosphine, tributylphosphine, triethylphosphite and diethyldiazodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), in thepresence of an inert organic solvent such as THF, toluene, ordichloromethane, under an inert atmosphere such as argon or nitrogen, toform the separate isomers XXIIIS' and XXIIIR' which may be converted tothe IS and IR isomers, respectively, as described in Scheme XV Part A.Alternatively, the isomer separation can be carried out at the stage ofXXXR and XXXS.

If desired, the phosphorous diamide XXVII may be converted directly intothe alcohols XXXR and XXXS by subjecting XXVII to a condensationreaction with aldehyde XXVIII in the presence of a base such as1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine, basic aluminaor a fluoride source such as described above or potassium or cesiumfluoride, to form a mixture of XXXR and XXXS.

In carrying out the Scheme XV Part C method, the diamine XXR (or XXS) isreacted with phosphorus trichloride at a temperature of within the rangeof from about 50° C. to about -80° C., preferably from about 0° C. toabout -80° C., employing a molar ratio of trichloride:XXR of within therange of from about 3:1 to about 0.8:1, preferably from about 1.5:1 toabout 1:1.

The condensation reaction of the phosphorus diamide XXVII with thealdehyde XXVIII is carried out employing a molar ratio of diamideXXVII:aldehyde XXVIII of within the range of from about 2:1 to about0.8:1, preferably from about 1.5:1 to about 1:1, and a molar ratio ofsilyl protecting compound:XXVII of within the range of from about 3:1 toabout 1:1, preferably from about 1.5:1 to about 1:1.

Reaction of the individual isomers XXIXS and XXIXR with the fluoridesource is carried out employing a molar ratio of fluoride source toXXIXS or XXIXR of within the range of from about 4:1 to about 1:1,preferably from about 2:1 to about 1.1:1.

Where the phosphorus diamide XXVII is converted directly to the isomersXXXR and XXXS (see Scheme XV Part C(1)), the condensation reaction ofXXVII with the aldehyde XXVIII and base or fluoride source as describedabove will be carried out essentially under similar conditionspreviously described for formation of XXIXS and XXIXR, and XXXS andXXXR.

The Mitsunobu displacement of XXXR and XXXS is carried out employing amolar ratio of dimethyldithiocarbamic acid or diethyl derivative, zincsalt or equivalent: XXXS or XXXR of within the range of from about 2:1to about 0.5:1, preferably from about 1.5:1 to about 0.6:1, and a molarratio of triphenylphosphine or equivalent:XXXR or XXXS of within therange of from about 4:1 to about 1:1, preferably from about 2:1 to about1:1.

A preferred method for forming the desired enantiomers of formula I isshown in Scheme XVI wherein a solution of the (R,R)-diamine XXR (or thecorresponding (S,S)-diamine XXS where the α-(R) product is desired) inan aprotic solvent such as toluene, benzene, dichloromethane or THF, andweak organic base such as triethylamine, pyridine ordiisopropylethylamine is created with phosphorus oxychloride to form theacid chloride XXXI which in solution with an inert organic solvent suchas THF, diethylether or dimethoxyethane is subjected to a couplingreaction with ##STR41## (prepared by reaction of analkylmethanesulfonate XXXIB with alkyllithium) to form the sulfonateXXXII (which is a novel intermediate in accordance with the presentinvention). Sulfonate XXXII is dealkylated by treatment with adealkylating agent such as tetrabutylammonium iodide, in the presence ofan inert organic solvent such as THF, diethylether or acetone, to formsulfonate XXXIII (which is a novel intermediate in accordance with thepresent invention) which is made to undergo dianion formation byreaction with a metalating agent such as n-butyllithium,sec-butyllithium, t-butyllithium or lithium diisopropylamide, under aninert atmosphere such as argon or nitrogen, in the presence of an inertorganic solvent such as hexane, THF or diethyl ether, and is thentreated with alkylating agent R¹ Hal in an inert organic solvent such asTHF, diethyl ether or hexane to form XXXIV (which is a novelintermediate in accordance with the present invention) optionally in thepresence of hexamethyl phosphoramide (HMPA) or tetramethylethylenediamine (TMEDA). XXXIV may be subjected to acid hydrolysis andion exchange to form the individual enantiomer IS, when Z is H.

As indicated, where the starting diamine XX is the (S,S)-enantiomer XXS,the final product will be the IR (R)-enantiomer, when Z is H.

In carrying out the Scheme XVI method, the phosphorus oxychloride willbe employed in a molar ratio to the diamine XXR of within the range offrom about 1.5:1 to about 0.8:1, preferably from about 1.1:1 to about0.9:1. The reaction will be carried out at a temperature within therange of from about -20° to about 40° C., preferably from about 0° toabout 25° C.

In forming ##STR42## (where alkyl is preferably ethyl or cyclohexyl) thealkylmethanesulfonate XXXIB is reacted with the alkyllithium or otherstrong base an a temperature within the range of from about -90° toabout 0° C., employing a molar ratio of alkyllithium:sulfonate XXXIB ofwithin the range of from about 1.2:1 to about 0.8:1, preferably fromabout 1.1:1 to about 0.9:1.

The ##STR43## compound XXXIA will be reacted with the acid chloride XXXIat a temperature within the range of from about -90° to about 0° C.,preferably from about -80° to about -30° C., employing a molar ratio ofLi compound XXXIA to XXXI of within the range of from about 4:1 to about1:1, preferably from about 2.5:1 to about 1.5:1.

The dealkylation of sulfonate XXXII is carried out employing a molarratio of iodide:XXXII of within the range of from about 1.5:1 to about0.9:1, preferably about 1:1.

In the dianion formation, sulfonate XXXIII is treated with the base at atemperature within the range of from about -100° to about 0° C.,preferably from about -90° to about -60° C., employing a molar ratio ofbase:XXXIII of within the range of from about 2:1 to about 0.8:1,preferably from about 1.5:1 to about 1:1.

The lithiated XXXIII compound is alkylated with R¹ Hal at a temperaturewithin the range of from about -100° to about 0° C., preferably fromabout -90° to about -60° C., employing a molar ratio of R¹ Hal:lithiatedhalide of within the range of from about 2:1 to about 1:1, preferablyfrom about 1.5:1 to about 1.1:1.

The alkylated sulfonate XXXIV is made to undergo acid hydrolysis bytreating XXXIV with strong aqueous acid, such as HCl, sulfuric or formicacids, and then with base such as KOH, NaOH or LiOH to form the majorisomer IS where (S) is at the α-center when Z is H. As indicated, wherethe starting (S,S)-diamine XXS is employed, the major isomer obtained isIR where (R) is at the α-center when Z is H.

An alternative preferred method for forming the desired enantiomers ofthe invention is shown in Scheme XVII. The starting aldehyde XXVIII (canbe prepared by reaction of the alcohol R¹ CH₂ OH with methylsulfoxide,and oxalyl chloride in the presence of weak organic base such astriethylamine, that is the Swern oxidation or other standard alcoholoxidations), is treated with (2S,4S)-(+)-pentanediol (or thecorresponding (2R,4R)-isomer) and p-toluenesulfonic acid in the presenceof an inert solvent such as benzene, toluene or dichloroethane, to formthe chiral acetal XL. Chiral acetal XL is subjected to an acetal openingreaction wherein acetal XL is reacted with a trialkylphosphite, such astriethylphosphite, in the presence of titanium (IV) chloride, and aninert organic solvent such as methylene chloride, toluene or benzene,under an inert atmosphere such as argon or nitrogen, to form the alcoholXLI which is oxidized via the Swern oxidation, pyridinium chlorochromate(PCC) or Jones reagent under standard conditions, to form XLII. The3-butene-2-one portion of XLII is eliminated by treating XLII withp-toluenesulfonic acid or methanesulfonic acid in the presence ofdioxane, or acetonitrile and water to form the diester XLIII which issubjected to a Mitsunobu displacement under the same conditions asdescribed for the conversion of XXXS/R to XXIIIS'/R'. See P. Rollin,supra, to form XLIV. Compound XLIV is dealkylated by reaction with adealkylating agent such as bromotrimethylsilane or iodotrimethylsilanein the presence of an inert organic solvent such as methylene chloride,benzene or toluene, under an inert atmosphere such as argon or nitrogen,to form the diacid XLV which is oxidized by treatment with hydrogenperoxide in formic acid, acetic acid or mixtures thereof or otheroxidants as described for Scheme XV, and then treated with alkali metalhydroxide such as KOH, NaOH or LiOH, or ion exchange resin as describedhereinbefore to form the (R)-enantiomer IR.

It will be appreciated that in carrying out the above method, where thealdehyde XXVIII is reacted with the (R,R)-diol, the final productobtained will be the α-(S)-enantiomer IS.

In carrying out the method of Scheme XVII, the (2S,4S)-(+)-pentanediolwill be reacted with the starting aldehyde XXVIII at a temperaturewithin the range of from about 25° to about 100° C., preferably fromabout 60° to about 90° C., employing a molar ratio of diol:XXVII ofwithin the range of from about 4:1 to about 0.8:1, preferably from about2:1 to about 1:1. The resulting chiral acetal XL is reacted with thetrialkylphosphite and titanium(IV)chloride or equivalent at atemperature within the range of from about -90° to about -20° C.,preferably from about -80° to about -40° C., employing a molar ratio ofphosphite:XL of within the range of from about 5:1 to about 1:1,preferably from about 3:1 to about 2:1, and a molar ratio ofphosphite:titanium tetrachloride of within the range of from about 3:1to about 1:1, preferably from about 1.2:1 to about 1.6:1, to formalcohol XLI.

The oxidation of alcohol XLI is carried out at a temperature within therange of from about -80° to about 0° C., and the elimination reactioninvolving XLII is carried out at a temperature within the range of fromabout 30° to about 150° C., preferably from about 80° to about 120° C.,employing a molar ratio of p-toluenesulfonic acid or equivalent:XLII ofwithin the range of from about 0.5:1 to about 0.005:1, preferably fromabout 0.1:1 to about 0.05:1.

The Mitsunobu displacement reaction is as described previously forScheme XV Part C.

Dealkylation of XLIV is carried out employing a molar ratio ofdealkylating agent:XLIV of within the range of from about 10:1 to about2:1, preferably from about 6:1 to about 4:1.

Scheme XVIII sets out a purification procedure wherein the desiredindividual enantiomers (salt thereof) is subjected to ion exchange (H⁺form) such as by treatment with AG 50-X8 ion exchange resin, to form thefree triacid IQ which is treated with an amine such as adamantanamine or(S)-(-)-α-methylbenzylamine (under an inert atmosphere such as argonwhere the latter amine is employed), in a molar ratio of amine:IQ withinthe range of from about 2.2:1 to about 1.9:1, preferably about 2:1, toform the corresponding bis-amine salt IQ' which is separated out byrecrystallization. The so-formed diamine salt IQ' may be treated withion exchange resin (M⁺ form) such as Ag50-X8 (K⁺ form) or basified withMOH (where M is K, Li or Na) to form the purified enantiomer. Aminesalts IQ' of chiral amines and racemic triacid I may be used to resolvethe racemate into α-(R) and (α)-S isomers by recrystallization.

If desired, the diamine salt IQ' may be treated with ion exchange resin(H⁺ form) to form the triacid IQ which may be treated with ion exchangeresin (M⁺ form) or basified with MOH to form the purified enantiomers,IS or IR.

Scheme XIX set out a reaction sequence for preparing prodrugs of thedesired enantiomer. As seen, the starting enantiomer IS (or IR) istreated with a silver salt such as silver nitrate to form the silversalt IAg which is alkylated by treatment of IAg (optionally in thepresence of 4A molecular sieves, anisole, thioanisole,2,6-di-t-butylpyridine and mixtures thereof) with alkylating agent XI toform triester LI.

The triester LI is subjected to solvolysis in water, or optionally awater-miscible solvent such as ethanol, methanol,2,2,2-trifluoroethanol, acetonitrile or mixtures of water and theorganic solvent, at 0° C. to 60° C., to form the diester LII which ismade to undergo salt formation by treatment of LII with an alkali metalphosphate buffer, such as potassium phosphate buffer, or ion exchange,to form the salt IS'.

The various acid and salt forms of the invention ID, IE, IF, IG, IL, IM,IN, IO, IP, IQ, IR, IS, IR', IS', LIIR, LIIS, IT and IU can beinterconverted by standard means, including ion exchange chromatography.It should be understood that all acids can be isolated either as salts(M=pharmaceutically acceptable cations such as Li⁺, Na⁺, K⁺, NH₄ ⁺), orfree acids (M=H).

Examples of starting alkylating agents that is R¹ X or R¹ Hal suitablefor use herein include the following which are either known in theliterature or are simple derivatives of known compounds prepared byemploying conventional procedures.

It will be appreciated that the R¹ X compounds listed in the followingtable represent all possible stereoisomers.

R¹ Hal where Hal is Cl, Br or I, or Otosyl or OSO₂ CF₃ is as follows inA. through F.

    __________________________________________________________________________    A.                                                                               ##STR44##                                                                     ##STR45##                                                                              R.sup.17        R.sup.18                                          1.          C.sub.2 H.sub.5 CH.sub.3                                          2.          CH.sub.3        C.sub.2 H.sub.5                                   3.          n-C.sub.3 H.sub.7                                                                             CH.sub.3                                          4.          CH.sub.3        n-C.sub.4 H.sub.9                                 5           t-C.sub.4 H.sub.9                                                                             CH.sub.3                                          (CH.sub.2).sub.s'                                                             s' = 4 to 6                                                                   7.          H               H                                                 8.          F               F                                                 9.          Cl              Cl                                                10.         CH.sub.2 F      CH.sub.3                                          11.         CHCH.sub.2      H                                                 12.         CF.sub.3 (CH.sub.2).sub.t                                                                     H                                                 t = 0 to 8                                                                    B.                                                                               ##STR46##                                                                     ##STR47##                                                                    alkyl(CH.sub.2).sub.t                                                         CH.sub.3 (CH.sub.2).sub.t where t is 0 to 8                                    ##STR48##                                                                     ##STR49##                                                                     ##STR50##                                                                     ##STR51##                                                                     ##STR52##                                                                     ##STR53##                                                                     ##STR54##                                                                    CF.sub.3 (CH.sub.2).sub.t                                                   10.                                                                              ##STR55##                                                                     ##STR56##                                                                     ##STR57##                                                                     ##STR58##                                                                     ##STR59##                                                                     ##STR60##                                                                  Examples 5 to 10, t = 0 to 8                                                  R.sub.1, R.sub.2 and R.sub.3 may be the same or different and can             be any of the radicals included in R.sup.6.                                   Examples 11 to 15                                                             t = 1 to 8                                                                    x = 3 to 8                                                                    C.                                                                               ##STR61##                                                                     ##STR62##                                                                  __________________________________________________________________________    D.                                                                               ##STR63##                                                                     ##STR64##                                                                            R.sup.21  R.sup.22   R.sup.22                                       1.        C.sub.2 H.sub.5                                                                         C.sub.2 H.sub.5                                                                          CH.sub.3                                       2.        CH.sub.3  CH.sub.3   C.sub.2 H.sub.5                                3.        CH.sub.3  C.sub.2 H.sub.5                                                                          C.sub.2 H.sub.5                                4.        C.sub.2 H.sub.5                                                                         C.sub.2 H.sub.5                                                                          C.sub.2 H.sub.5                                5.        CH.sub.3  C.sub.2 H.sub.5                                                                          CH.sub.3                                       6.        CH.sub.3  H          CH.sub.3                                       7.        CH.sub.3  CH.sub.3   H                                              8         H         H          H                                              9         CF.sub.3  CH.sub.3   CH.sub.3                                       10.       CH.sub.3  CF.sub.3   CH.sub.3                                       11.       CH.sub.3  CH.sub.3   CF.sub.3                                       12.       CF.sub.3  CF.sub.3   CH.sub.3                                       13.       CF.sub.3  CF.sub.3   CF.sub.3                                       E.                                                                               ##STR65##                                                                     ##STR66##                                                                           R.sup.24   R.sup.25  R.sup.26                                        1.       H          I         H                                               2.       H          H         I                                               3.       H          CH.sub.3  CH.sub.3                                        4.       CH.sub.3 S CH.sub.3  H                                               5.       F          CH.sub.3  H                                               6.       CH.sub.3   CH.sub.3  H                                               7.       H          CH.sub.3  CH.sub.3                                        8.       H          CH.sub.3  Cl                                              9.       H          CF.sub.3  H                                               10.      H          Cl        H                                               11.      H          CH.sub.3  (CH.sub.3).sub.3 Si                             12.      H          CH.sub.3  F                                               13.      H          CF.sub.3  CH.sub.3                                        14.      H          CH.sub.3  CF.sub.3                                        F.                                                                              Other examples of R.sup.1 include the following                                ##STR67##                                                                     ##STR68##                                                                     ##STR69##                                                                     ##STR70##                                                                     ##STR71##                                                                     ##STR72##                                                                     ##STR73##                                                                  In Examples 1 to 5, m is 1 to 8.                                              In Examples 6 and 7, m is 0 to 8.                                                ##STR74##                                                                     ##STR75##                                                                  10.                                                                              ##STR76##                                                                     ##STR77##                                                                     ##STR78##                                                                     ##STR79##                                                                  In Examples 8 to 13, n is 1 to 8.                                                ##STR80##                                                                     ##STR81##                                                                     ##STR82##                                                                     ##STR83##                                                                     ##STR84##                                                                     ##STR85##                                                                  20.                                                                             CH.sub.3C  C(CH.sub.2).sub.n  (n = 4-12)                                       ##STR86##                                                                  X = H, F, CH.sub.3                                                            n is 1 or 2                                                                   m is 0 to 8                                                                     CH.sub.3C  C(CH.sub.2).sub.nC  C(CH.sub.2).sub.m  (n = 0-10) (m is 0 to       8)                                                                             ##STR87##                                                                  R.sup.40 = H, alkyl, cycloalkyl, or aryl such as                              methyl, ethyl, isopropyl, pentyl, phenyl                                      and cyclopentyl                                                               R.sup.41 = alkyl such as methyl, ethyl or halo                                such as Cl or F                                                                  ##STR88##                                                                     ##STR89##                                                                     ##STR90##                                                                     ##STR91##                                                                     ##STR92##                                                                     ##STR93##                                                                  __________________________________________________________________________

    __________________________________________________________________________     ##STR94##                                                                      R.sup.42                                                                          R.sup.43                                                                          R.sup.44                                                                          R.sup.45                                                                         R.sup.46     ,t                                              __________________________________________________________________________    30)                                                                             H   H   H   H  n-C.sub.3 H.sub.7                                                                          3                                               31)                                                                             H   H   H   H  n-C.sub.4 H.sub.9                                                                          3                                               32)                                                                             H   H   H   H  (CH.sub.3).sub.2CCH                                                                        4                                               33)                                                                             H   H   H   H  (CH.sub.3).sub.2CCHCH.sub.2                                                                2                                               34)                                                                             CH.sub.3                                                                          H   CH.sub.3                                                                          H                                                                                 ##STR95##   3                                               35)                                                                             H   H   CH.sub.3                                                                          H  (CH.sub.3).sub.2CHCH.sub.2O                                                                3                                               36)                                                                             H   CH.sub.3                                                                          CH.sub.3                                                                          H  n-C.sub.3 H.sub.7                                                                          3                                               37)                                                                             CH.sub.3 O                                                                        H   H   H  n-C.sub.4 H.sub.9                                                                          3                                               38)                                                                             H   H   H   H  (CH.sub.3).sub.2CCH                                                                        3                                               39)                                                                             H   H   H   H  (CH.sub.3).sub.2CCHCH.sub.2                                                                4                                               40)                                                                             CH.sub.3                                                                          H   H   H                                                                                 ##STR96##   5                                               41)                                                                             F   H   CH.sub.3                                                                          H  n-C.sub.3 H.sub.7                                                                          3                                               42)                                                                             CH.sub.3                                                                          H   F   H  n-C.sub.4 H.sub.9                                                                          3                                               43)                                                                             H   CH.sub.3                                                                          H   CH.sub.3                                                                         (CH.sub.3).sub.2CCH                                                                        3                                               44)                                                                             H   H   H   CF.sub.3                                                                         (CH.sub.3).sub.2CCHCH.sub.2                                                                3                                               45)                                                                             H   H   H   F                                                                                 ##STR97##   3                                               46)                                                                             H   Cl  Cl  H  CH.sub.2CHCH.sub.2                                                                         3                                               47)                                                                             CH.sub.3                                                                          H   H   H  C.sub.4 H.sub.9                                                                            3                                               48)                                                                             H   H   OH  H  C.sub.3 H.sub.7                                                                            3                                               49)                                                                             H   H   OCH.sub.3                                                                         H  C.sub.3 H.sub.7                                                                            4                                               50)                                                                             H   H   CH.sub.3                                                                          H  C.sub.3 H.sub.7                                                                            3                                               51)                                                                             H   OH  H   H  C.sub.3 H.sub.7                                                                            3                                               52)                                                                             H   OCH.sub.3                                                                         H   H  C.sub.3 H.sub.7                                                                            4                                               53)                                                                             H   CH.sub.3                                                                          H   H  C.sub.3 H.sub.7                                                                            3                                               __________________________________________________________________________    R.sup.2 = H, OMetal, alkyl, aryl                                              R.sup.3 = H, metal ion or alkyl                                               R.sup.4 =H, metal ion or alkyl                                                54)                                                                              ##STR98##                                                                  55)                                                                              ##STR99##                                                                  56)                                                                              ##STR100##                                                                 Re 54) to 56)                                                                 R is n-C.sub.3 H.sub.7, n-C.sub.4 H.sub.9, (CH.sub.3).sub.2CCH,               CH.sub.3CHHCH.sub.2,                                                          (CH.sub.3).sub.2CHCHCH.sub.2, CH.sub.2CHCH.sub.2 O, (CH.sub.3).sub.2CHO,      (CH.sub.3).sub.2 CHCH.sub.2 O,                                                 ##STR101##                                                                   CH.sub.2CHCH.sub.2, CH.sub.2CHCH.sub.2 CH.sub.2, phenyl, pyridyl              57)                                                                              ##STR102##                                                                 Z = Cl, F, alkyl such as methyl, ethyl,                                       propyl or allyl                                                               n = 0, 1, 2                                                                   p.sup.1 = 0-8                                                                 m = 2-8                                                                       In compounds 49) to 52)                                                       R.sup.3 = H, metal ion or alkyl                                               R.sup.4 = H, metal ion, alkyl or aryl                                         R.sup.2 = H, Ometal, alkyl, aryl                                              58)                                                                              ##STR103##                                                                 X is O, S NH, SO, SO.sub.2, CR.sup.5 R.sup.6, CO                              R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently     H,                                                                            halogen, C.sub.1 -C.sub.5 alkyl, C.sub.1 -C.sub.5 alkenyl, C.sub.1            -C.sub.5 alkoxy,                                                              aryl, arylalkyl, aryloxy; for R.sup.5 and R.sup.6, halogen                    can be fluorine only.                                                          ##STR104##                                                                    ##STR105##                                                                    ##STR106##                                                                    ##STR107##                                                                    ##STR108##                                                                    ##STR109##                                                                    ##STR110##                                                                    ##STR111##                                                                   R is as defined for 54) to 56).                                                ##STR112##                                                                    ##STR113##                                                                    ##STR114##                                                                    ##STR115##                                                                    ##STR116##                                                                    ##STR117##                                                                    ##STR118##                                                                   X = bond, O, NH, S, CH.sub.2, CR.sup.5 R.sup.6                                p = 1 to 8                                                                    n = 0 to 4; R.sup.1, R.sup.2, R.sup.5 and R.sup.6 are independently           halogen, alkyl, alkenyl, alkoxy, aryl, H, aryloxy;                            for R.sup.5 and R.sup.6 halogen can be fluorine only.                         __________________________________________________________________________

Preferred are enantiomers of compounds of formula I in the (S)configuration of the above preferred compounds, that is ##STR119##wherein Z is H, R¹ is preferably Ar¹ --O--Ar² --(CH₂)_(p) --, R³, R⁵ andR⁴ are an alkali metal such as K or Na.

More preferred are prodrug (P.D.) esters of the (S)-enantiomer (IS),that is ##STR120##

Most preferred are compounds of formula IS where R¹ is

    Ar.sup.1 --O--Ar.sup.2 --(CH.sub.2).sub.p --

R⁴ is an alkali metal such as K or Na

Z is H and Prodrug ester is bis(pivaloyloxymethyl) ester.

In addition, in accordance with the present invention new intermediatesare provided which are prepared as described above, and have thefollowing formulae: ##STR121##

The compounds of Formula I of the invention inhibit cholesterolbiosynthesis by inhibition of de novo squalene production. Thesecompounds inhibit the squalene synthetase enzyme and, in addition, someof the compounds of Formula I of the invention inhibit other enzymes inthe pathway from isopentenyl diphosphate to squalene, that is, farnesyldiphosphate synthetase and isopentenyl diphosphate-dimethylallyldiphosphate isomerase.

The compounds of the invention are useful in treatinghyperlipoproteinemia, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, combined hypercholesterolemia andhypertriglyceridemia, and/or in preventing development of and/ortreating atherosclerosis. Thus, the compounds of the invention may beused to treat diseases such as chylomicronemia syndrome, Type Ihyperlipoproteinemia, familial combined hyperlipoproteinemia, familialhypertriglyceridemia, mixed hyperlipoproteinemia, familialhypercholesterolemia and Type III hyperlipoproteinemia and/oratherosclerosis.

In addition, the compounds of the invention may increase plasma highdensity lipoprotein cholesterol levels.

The compounds of the invention may also be useful in inhibitingformation of gallstones, treating hepatitis D (by virtue of proteinprenyltransferase inhibition, Glenn et al, Science, Vol. 256, pp.1331-1333, May 29, 1992), treating tumors, lowering blood pressure,lowering blood sugar, treating diabetes mellitus, treating inflammation,as a diuretic, as an inotropic agent, as an anti-arthritic(antirheumatic) agent, in treating other diseases of calcium andphosphate metabolism including treatment of bone resorption, Paget'sdisease, osteoporosis, calcification of joints, implants and metastasis,as antitartar and anticalculus agents in toothpastes and mouthwashes,treating various stones and calculi, treating sickle cell anemia,treating hypoxia and ischemic tissue, and as an anti-ameobal agent, aswell as for use in complexes with technetium-99m and radioiodinatedderivatives for use as diagnostics.

U.S. application Ser. No. 774,957, filed Oct. 11, 1991, discloses thatpost-translational modification of CAAX box containing proteins may beinhibited by administering a protein-prenyl transferase inhibitor whichinhibits the transfer of the prenyl group [such as farnesyl (in the caseof ras oncogene products), geranyl or geranylgeranyl] to the cysteine ofthe CAAX box by the protein-prenyl transferase enzyme. Theprotein-prenyl transferase inhibitor will block the protein-prenyltransferase enzyme from catalyzing the transfer of the prenyl group (forexample, farnesyl, geranyl or geranyl-geranyl) from the prenylpyrophosphate to the cys residue of the CAAX box, such as the ras p21cys, or to the CAAX box cysteine of other CAAX box containing proteins.In the case of ras p21 oncogene products, inasmuch as the cys is notfarnesylated, in the presence of the protein prenyl transferaseinhibitor, it cannot effect interaction of the ras protein with themembrane so that neoplastic transformation of the cell will beprevented. In this manner protein-prenyl transferase inhibitors preventneoplastic transformation of the cell, thereby acting as an anti-canceragent for the treatment of and/or prevention of ras-related tumors.

Examples of CAAX box containing proteins which have been demonstrated orare believed to undergo prenylation include, but are not limited to,ras, nuclear lamins, α or γ subunits of heterotrimeric G-proteins,γ-subunits of retinal transducin, G25K and K-rev p21, and proteinfamilies including rho, rap, rac, ral, and rab.

The present invention includes a method for blocking or preventing theprenylation of CAAX box containing proteins such as rasoncogeneproducts, and thereby inhibit disease promoting effects of the CAAX boxcontaining protein or more specifically prevent and/or treat ras-relatedtumors, by administering to a patient in need of treatment a therapeuticamount of a compound of Formula I of the invention which serves as aprotein-prenyl transferase inhibitor.

The Formula I protein-prenyl transferase inhibitors, unlike HMG CoAreductase inhibitors, will interfere with prenylation of the rasoncogene products and inhibit their transforming activity, yet may ormay non interfere with the synthesis of FPP, a precursor in thesynthesis of ubiquinones, dolichols and Haem A.

The compounds of the invention may also be employed in combination withan antihyperlipoproteinemic agent, hypocholesterolemic agent, and/orhypotriglyceridemic agent, and/or antiatherosclerotic agent such as oneor more HMG CoA reductase inhibitors, for example, pravastatin,lovastatin, simvastatin, velostatin, fluvastatin, rivastatin, compactin,SDZ-63, 370 (Sandoz), CI-981 (W-L), HR-780, L-645,164, CL-274,471,dalvastatin, α-, β-, and γ-tocotrienol, (3R, 5S,6E)-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid, L-arginine salt,(S)-4-[[2-[4-(4-fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt, BB-476, (British Biotechnology), dihydrocompactin,[4R-[4α,6β(E)]]-6-[2-[5-(4-fluorophenyl)-3-(1-methylethyl)-1(2-pyridinyl)-1H-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one,and/or 1H-pyrrole-1-heptanoic acid,2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]calciumsalt [R-(R*,R*)]; one or more fibric acid derivatives such asclofibrate, bezafibrate, Lopid(gemfibrozil) one or more othercholesterol biosynthesis inhibitors, such as NB-598,N-(1-oxododecyl)-4α,10-dimethyl-8-aza-trans-decal-3β-ol,2,4-undecadienoic acid,11-[3-(hydroxymethyl)-4-oxo-2-oxetanyl]-3,5,7-trimethyl-,[2R-[2α(2E,4E,7R*),3β]]; one or more bile acid sequestrants, forexample, cholestyramine, colestipol, polidexide (DEAESephadex); one ormore antioxidants, for example probucol and Vitamin E; and/or one ormore other lipid lowering and/or antiatherosclerotic agents, for examplenicotinic acid or derivatives thereof, neomycin, p-aminosalicylic acid,probucol, hydroxypropylmethylcellulose, LS-2904, ethanol,2-[[1-methyl-2-[3-(trifluoromethyl)phenyl]ethyl]amino]benzoate (ester).

The above compounds to be employed in combination with the squalenesynthetase inhibitor of the invention will be used in amounts asindicated in the Physicians' Desk Reference (PDR).

The compounds of the invention may also be employed with sodium laurylsulfate of other pharmaceutically acceptable detergents to enhance oralbioavailability of such compounds.

Inhibition of squalene synthetase may be measured by the followingprocedure.

Rat liver microsomal squalene synthetase activity is measured usingfarnesyl diphosphate as substrate and quantitating squalene synthesisusing gas chromatographic analysis. The assay was developed by modifyingconditions originally described by Agnew (Methods in Enzymology 110:357,1985).

A further aspect of the present invention is a pharmaceuticalcomposition consisting of at least one of the compounds of theinvention, such as Formula I, in association with a pharmaceuticalvehicle or diluent. The pharmaceutical composition can be formulatedemploying conventional solid or liquid vehicles or diluents andpharmaceutical additives of a type appropriate to the mode of desiredadministration. The compounds can be administered to mammalian speciesincluding humans, monkeys, dogs, etc., by an oral route, for example, inthe form of tablets, capsules, granules or powders, or they can beadministered by a parenteral route in the form of injectablepreparations. The dose for adults is preferably between 200 and 2,000 mgper day, which can be administered in a single dose or in the form ofindividual doses from 1-4 times per day.

A typical capsule for oral administration contains active ingredient(250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture ispassed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.

A typical injectible preparation is produced by asceptically placing 250mg of sterile active ingredient into a vial, asceptically freeze-dryingand sealing. For use, the contents of the vial are mixed with 2 mL ofphysiological saline, to produce an injectible preparation.

The following Examples represent preferred embodiments of the presentinvention.

Introduction to Experimental

All temperatures are reported in degress Centigrade.

¹ H and ¹³ C chemical shifts are reported as δ-values with respect toMe₄ Si (δ=0). ³¹ P spectra were obtained using 85% H₃ PO₄ as an externalreference (δ=0). Coupling constants J are reported in Hz. For massspectra (mass spec or MS) the value utilized for the parent M is that ofthe salt form which was prepared and tested.

All reactions were carried out under an atmosphere of dry argon ornitrogen. The following reagents and solvents were distilled prior touse from the indicated drying agents, where applicable: CH₂ Cl₂,2,4,6-collidine, and diisopropylamine (CaH₂); THF and diethyl ether (K,benzophenone); N,N-diethyltrimethylsilylamine and oxalyl chloride.Benzene was passed through neutral alumina (activity I) and stored over4A-molecular sieves. Lithium bromide was dried at 100° C. over P₂O₅.(E,E)-Farnesol was purchased from Aldrich Chemical Company.

TLC was performed on E. Merck Silica Gel 60 F-254 plates (0.25 mm) or E.Merck Cellulose F plates (0.1 mm). Flash chromatography was carried outusing E. Merck Kieselgel 60 (230-400 mesh).

Reverse-phase chromatographic purification of salts or mixed ester saltswas carried on CHP20P gel or SP207SS gel, highly porous,polystyrenedivinyl benzene copolymers available from Mitsubishi ChemicalIndustries. The indicated general procedure was followed: An FMI ModelRP-SY pump was utilized for solvent delivery. A column of CHP20P orSP207SS (2.5 cm diameter, 12-22 cm height) ws slurry packed and washedwith water (500-1000 mL), and a basic, aqueous solution of the crudesalt was applied to the top of the column. Typically, the column waseluted with water, followed by a gradient composed of increasingconcentrations of acetonitrile or methanol in water. The gradient wascreated by placing the tip of a tightly stoppered separatory funnelcontaining 300-500 mL of the organic solvent, or an aqueous-, organicmixture, just beneath the surface of a reservoir containing 300-500 mLof pure water. To start the gradient, the stopcock of the separatoryfunnel was opened, so that as the solvent was withdrawn by the pump fromthe reservoir, it was replaced with the solvent from the separatoryfunnel. HPLC-grade solvents were employed. Fractions were collected(10-15 mL each) at a flow rate of 5-10 mL per minute. Those fractionsthan contained pure product as judged by TLC or HPLC were pooled, theorganic solvents were evaporated and the aqueous residue was lyophilizedto dryness.

EXAMPLE 1

(E,E)-(6,10,14-Trimethyl-2-phosphono-5,9,13-pentadecatriene-1-sulfonicacid, trisodium salt

A. Bishomofarnesol

(1) (E,E)-3,7,11,-Trimethyl-2,6,10-dodecatrieyl bromide (farnesylbromide)

A solution of 1.00 g (4.5 mmol) of (E,E)-farnesol (Aldrich, furtherpurified by flash chromatography) in 10 mL of distilled ether at 0° C.under argon in the dark was treated dropwise with a solution of 195 μL(2.05 mmol, 0.45 eq.) of PBr₃ in 2 mL of diethyl ether (ether). Theresultant mixture was stirred at 0° C. for one hour, then quenched withwater and separated. The organic phase was washed with 5 mL of H₂ O, 5ml of saturated NaHCO₃, and 5 mL of brine, dried over Na₂ SO₄ andevaporated to give 1.26 g (98%) of crude bromide as a clear oil.

TLC Silica (2:8 ethyl acetate:hexane) Rf=O.69.

¹ H NMR (CDCl₃, 270 MHz): δ5.52 (t, 1H, J=8.5 Hz), 5.08 (m, 2H), 4.01(d, 2H, J=8.5 Hz), 2.20-1.90 (m, 8H), 1.73 (s, 3H), 1.68 (s, 3H), 1.60(s, 6H) ppm.

(2) (E,E)-5,9,13-Trimethyl-4,8,12-tetradecatrienoic acid,1.1-dimethylethyl ester

To a solution of 9.60 mL (68.5 mmol, 1.5 eq.) of diisopropylamine in 100mL of tetrahydrofuran (THF) at -78° C. under argon was added 28.2 mL(45.0 mmol, 1.0 eq.) of 1.6M n-butyllithium in hexanes over 20 minutes.After warming to 0° C. for 15 minutes, the solution was recooled to -78°C. and 6.05 mL (45 mmol, 1.0 eq.) of t-butyl acetate was added over 20minutes. After an additional 15 minutes, 16.0 mL (92 mmol, 2.05 eq.) ofhexamethylphosphoramide (HMPA) was added, followed by a solution of12.53 g (45.0 mmol) of Part A (1) farnesyl bromide in 100 mL of THF over20 minutes. The reaction was stirred at -78° C. for 2.5 hours, quenchedwith saturated NH₄ Cl and allowed to warm to room temperature. Afterdiluting with 400 mL of ethyl acetate, the mixture was washed with four100 mL portions of water, and 200 mL of brine, dried over MgSO₄ andevaporated to provide 12.96 g of crude product as a yellow oil.Purification by flash chromatography on 1 kg of silica gel, eluted with1:9 ethyl acetate:petroleum ether afforded 9.39 g (65%) of titlecompound as a pale yellow oil.

TLC Silica gel (2:98 ethyl acetate:hexane) R_(f) =0.16.

IR(neat) 2977, 2925, 2857, 1733, 1452, 1368, 1258, 1149 cm⁻¹.

¹ H NMR(CDCl₃, 270 MHz): δ5.10 (m, 3H), 2.25 (m, 4H), 2.10-1.90 (m, 8H),1.68 (s, 3H), 1.62 (s, 3H), 1.59 (s, 6H), 1.44 (s, 9H) ppm.

Mass spec. (CI-CH₄ /N₂ O) (+ ions) m/e 165 (M+H-C₄ H₈), 247, 183, 137,68, 67. (- ions) m/e 319 (M-H), 279, 251, 100.

(3) Bishomofarnesol

To a stirred solution of 5.00 g (15.6 mmol) of Part (2) compound in 45mL of dry diethyl ether at 0° C. under argon was added 592 mg (15.6mmol, 1 mol-eq.) of lithium aluminum hydride, and the resultingsuspension was stirred at room temperature for 20 hours. After coolingto 0° C., the reaction was quenched by treating with 5 mL of H₂ O, 5 mLof 15% NaOH, and 15 mL of H₂ O and stirring the suspension for 1/2 hour.After adding Na₂ SO₄, the slurry was filtered through Celite, washingwell with diethyl ether and evaporated to obtain 3.62 g of crudeproduct. Purification by flash chromatography on 300 g of silica gel,eluted with 1:9 ethyl acetate:petroleum ether provided 3.516 g (90%) ofbishomofarnesol as a colorless liquid.

TLC Silica gel (2:8 ethyl acetate (EtOAc):hexane) R_(f) =0.19.

IR(neat) 3330, 2964, 2926, 2873, 2958, 1448, 1384, 1107, 1059, 401 cm⁻¹.

¹ H NMR(CDCl₃, 270 MHz): δ5.10 (m, 3H), 3.63 (t, 2H, J=6.5 Hz),2.20-1.90 (m, 10H), 1.68 (s, 3H), 1.62 (s, 3H), 1.60 (s+m, 8H) ppm.

Mass Spec (CI-CH₄ /N₂ O, + ions) m/e 251 (M+H), 249 (M+H-H₂), 137, 123,109, 69.

A¹. Bishomofarnesol (alternative preparation)

(1) (E,E)-(3,7,11-Trimethyl-2,6,10-undecadienyl)propanedicarboxylicacid, diethyl ester

To a suspension of 1.62 g (40.5 mmol, 3 eq.) of a 60% suspension ofsodium hydride in mineral oil (washed three times with pentane) in 150mL of tetrahydrofuran at room temperature under argon was slowly added6.15 mL (40.5 mmol, 3 eq.) of diethyl malonate. The resulting solutionwas stirred for 0.5 hours, then treated with a solution of 3.83 g (13.5mmol) of farnesyl bromide in 10 mL of tetrahydrofuran. After stirringfor 6 hours, the reaction was quenched with saturated NH₄ Cl and dilutedwith 300 mL of diethyl ether. The organic layer was washed with two 100mL portions of water and 100 mL of brine, dried over MgSO₄ andevaporated and the bulk of the diethyl malonate removed by spinningunder high vacuum to afford 4.29 g (87%) of crude title product.

TLC Silica gel (ethyl acetate:hexane 1:9) R_(f) =0.37.

(TLC shows slight amount of diethyl malonate and a second by-product.)

(2) (E,E)-5,9,13-Trimethyl-4,8,12-tetradecatrienoic acid, ethyl ester

A mixture of 4.103 g (11.2 mmol) of Part A¹ (1) diester, 200 μL (11.2mmol, 1 eq.) of water and 950 mg (22.4 mmol. 2 eq.) of lithium chloridein 20 mL of dimethyl sulfoxide was heated at reflux (˜190° C.) for fourhours. After cooling, the reaction mixture was diluted with 180 mL of a1:1 mixture of diethyl ether:petroleum ether and washed with five 50 mLportions of water and 50 mL of brine, dried over MgSO₄ and evaporated toyield 3.623 g of crude product as a yellow-orange oil. Kugelrohrdistillation at 180° C. (meter setting) and 0.025 mm allowed thecollection of 2.100 g of a pale yellow oil, which was, however, stillcontaminated (by TLC). The distillation, therefore, is unnecessary andshould not be performed. Flash chromatography on 180 g of silica gel,eluted with 3:97 ethyl acetate:petroleum ether provided 1.844 g (56%) ofdesired title product as a pale yellow oil.

TLC Silica gel (ethyl acetate:hexane 5:95) R_(f) =0.27.

¹ H-NMR (CDCl₃, 270 MHz): δ5.08 (m, 3H), 4.12 (q, 2H, J=6.7 Hz), 2.31(m, 4H), 2.10-1.90 (m, 8H), 1.67 (s, 3H), 1.62 (s, 3H), 1.59 (s, 6H),1.25 (t, 3H, J=6.7 Hz), ppm.

(3) Bishomofarnesol

A solution of 7.05 g (24 mmol) of Part A¹ (2) monoester in 65 mL of drydiethyl ether at 0° C. under argon was treated in portions with 915 mg(24 mmol) of lithium aluminum hydride and stirred at room temperaturefor three hours. After cooling to 0° C., the reaction was quenched with7 mL of water, 7 mL of 15% NaOH; then stirred for 15 minutes. Additional21 mL of water was added, and the reaction was stirred 0.5 hours, thendried with Na₂ SO₄. The mixture was filtered through Celite, washingwell with diethyl ether, and evaporated to give 5.665 g of a colorlessoil. Purification by flash chromatography on silic gel eluted with 15:85ethyl acetate:petroleum ether provided 5.23 g (87%) of title compound asa colorless oil.

TLC Silica gel (2:8 ethyl acetate:hexanes) R_(f) =0.21.

IR(neat) 3330, 2964, 2926, 2873, 2858, 1448, 1384, 1107, 1059, 401 cm⁻¹.

¹ H-NMR (CDCl₃, 270 MHz): δ5.10 (m, 3H), 3.63 (t, 2H, J=6.5 Hz),2.20-1.90 (m, 10H), 1.68 (s, 3H), 1.62 (s, 3H), 1.60 (s+m, 8H), ppm.

Mass Spec (CI-CH₄ /N₂ O, + ions) m/e 251 (M+H), 249 (M+H-H₂), 137, 123,109, 69.

B. (E,E)-5,9,13-Trimethyl-4,8,12-tetradecatrien-1-ol, methanesulfonateester

To a stirred solution of 2.02 g (8.07 mmol) of bishomofarnesol (preparedas described in Example 1, Part A) in 20 mL of dichloromethane at 0° C.was added 2.2 mL (16.1 mmol) of triethylamine followed by 0.69 mL (8.90mmol) of methanesulfonyl chloride, dropwise over 15 mintues. Afterstirring for 1.5 hours at 0° C., the reaction was diluted withdichloromethane, washed with 20 mL each of 10% HCl, saturated NaHCO₃ andbrine, dried (MgSO₄) and evaporated to give 2.71 g (100%) of the crudetitle mesylate as a colorless oil.

TLC Silica gel (CH₂ Cl₂) R_(f) =0.46.

¹ H NMR (CDCl₃, 270 MHz): δ5.09 (t, 3H, J=6.5 Hz), 4.21 (t, 2H, J=7.0Hz), 2.99 (s, 3H), 2.20-1.90 (m, 10H), 1.78 (quint, 2H, J=7.0 Hz), 1.65(s, 3H), 1.61 (s, 3H), 1.60 (s, 6H),

C. (E,E)-14-Iodo-2,6,10-trimethyl-2,6,10-tetradecatriene

The crude Example 1, Part B mesylate prepared from 441.1 mg (1.76 mmol)of the corresponding alcohol according to the procedure of Example 1,Part B, was dissolved in 5 mL of acetone and treated with 530 mg (3.52mmol) of sodium iodide. The reaction was allowed to stir for 16 hours atroom temperature followed by 5 hours at reflux. The suspension wasdiluted with hexane and stirred with dilute aqueous sodium bisulfite todischarge to yellow color. The organic layer was washed with water andbrine, dried (MgSO₄), and evaporated to provide 577 mg of crude product.Flash chromatography on 35 g of silica gel eluted with hexane gave 550.9mg (87%) of title iodide as a colorless liquid.

TLC Silica gel (hexane) R_(f) =0.31.

¹ H NMR (CDCl₃, 270 MHz): δ5.09 (m, 3H), 3.16 (t, 2H, J=7.0 Hz),2.20-1.90 (m, 10H), 1.85 (quint., 2H, J=6.5 Hz), 1.67 (s, 3H), 1.63 (s,3H), 1.59 (s, 6H) ppm.

Mass Spec (CI-CH₄ /N₂ O, + ions) m/e 361, 359 (M+H), 137.

D. (Diethoxyphosphinyl)methanesulfonic acid, ethyl ester

A solution of ethyl methanesulfonate (4.27 mL, 40.3 mmol) in 100 mL ofdry THF was treated at -78° C. with 19.3 mL (44.4 mmol) of n-BuLi inhexane. After 15 min. diethyl chlorophosphate (3.30 ml, 22.2 mmol) wasadded. The solution was kept at -78° C. for 0.5 h and allowed to stay at-50° C. for 1 h. Saturated ammonium chloride (75 mL) was added to thesolution and the mixture warmed to room temperature. The mixture wasconcentrated (THF removed), diluted with water and extracted withmethylene chloride (3×70 mL). The combined organic fractions were dried(MgSO₄), concentrated and purified by distillation to yield 3.86 g (70%)of title compound.

b.p. 120°-130° C., 1 mm Hg.

¹ H NMR (270 MHz, CDCl₃) δ4.40 (q, 2H, J=7.0 Hz) 4.20 (m, 4H) 3.80 (d,2H, J=17.2 Hz) 1.40 (t, 3H, J=7.1 Hz) 1.25 (t, 6H, J=7.0 Hz).

Ref. Carretero, J. C.; Demillequ, M.; Ghosez, L. Tetrahedron Vol. 43,1987, pp 5125.

E.(E,E)-1-(Diethoxyphosphinyl)-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, sodium salt

To a suspension of 192 mg (8.00 mmol) of NaH in 6 mL of dry DMF at 0° C.under argon was added 2.16 g (8.33 mmol) of Part D sulfonate over 15min. to give a yellow solution. The reaction was allowed to warm to roomtemperature and stir for 0.5 h when 1.00 g (2.77 mmol) of Part C iodidewas added in one portion. The reaction mixture was stirred for 18 h whenit was quenched with 10 mL of saturated NaCl solution and diluted with50 mL of ethyl acetate. The layers were separated, the organics dried(Na₂ SO₄) and evaporated to provide a crude glass. The glass wasdissolved with 2.0 mL of 1M NaOH solution and purified by MPLC on acolumn of CHP20P gel (2.5 cm diam. ×15 cm height) eluting with water(150 mL), followed by a gradient created by the gradual addition of 400mL of acetonitrile to a reservoir of 250 mL of water. Approximately 8 mLfractions were collected. The aqueous solution was concentrated andlyophilized to provide 0.78 g (57%) of title compound as a glass.

TLC Silica gel (8:1:1 propanol/conc. NH₃ /water) R_(f) =0.75.

IR (film) 3476 2921, 1664, 1444, 1383, 1241, 1029, 968, 815 cm⁻¹.

¹ H NMR (CDCl₃, 270 MHz): δ5.10 (m, 3H) 4.10 (m, 4H) 3.40 (dt, 1H,J=19.5, 6.0 Hz) 2.10-1.80 (m, 12H) 1.65 (s, 3H) 1.60 (m, 2H) 1.55 (s,9H) 1.30 (t, 6H, J=6.0 Hz) ppm.

Mass Spec (FAB, + ions) m/e 510 (M+Na).

F. (E,E)-6,10,14-Trimethyl-1-phosphono-5,9,13-pentadecatriene-1-sulfonicacid, trisodium salt

To a stirred solution of 0.75 g (1.50 mmol) of Part E salt in 8 mL ofdichloromethane at room temperature was added 0.54 g (4.50 mmol) of2,4,6-collidine followed by 0.82 g (5.35 mmol) of bromotrimethylsilane.The reaction was allowed to stir at room temperature for 14 h when thesolvent was evaporated and the semisolid residue pumped (≈1 mm pressure)for 0.5 h. The residue was dissolved by adding 6.6 mL (6.60 mmol), of 1MNaOH solution then diluting with 15 mL of water. The solution was freezedried to provide an off white solid. The solid was purified by MPLC on acolumn of CHP20P gel (2.5 cm diam. ×15 cm height) eluting with water(150 mL) followed by a gradient created by the gradual addition of 400mL of acetonitrile to a reservoir of 250 mL of water. Approximately 10mL fractions were collected. The acetonitrile was removed under reducedpressure and the aqueous solution was lyophilized to provide 0.34 g(46.5%) of the title compound as a white lyophilate.

TLC Silica gel (5:4:1 n-propanol/conc. ammonia/water) R_(f) =0.75.

IR (KBr) 3438, 2966, 2926, 2859, 1636, 1449, 1206, 1137, 1110, 976 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz): δ5.15 (t, 1H, J=7.0 Hz) 5.06 (q, 2H, J=7.0 Hz)2.77 (ddd, 1H, J=18.2, 7.0, 4.7 Hz) 2.10-1.80 (m, 12H) 1.54 (s, 3H) 1.49(s, 3H) 1.47 (s, 6H) 1.50 (m, 2H) ppm.

Mass Spec (FAB, + ions) m/e 475 (M+H), 453 (MNa+2H).

Anal. Calc'd for C₁₈ H₃₀ O₆ Na₃ PS+1.70 H₂ O: C, 42.80; H, 6.67; P,6.13: S, 6.35 Found: C, 42.80; H, 7.01; P, 6.24; S, 6.56.

EXAMPLE 1A

(E,E)-6,10,14-Trimethyl-1-phosphono-5,9,13-pentadecatriene-1-sulfonicacid, trisodium salt

A. Methanesulfonic acid, cyclohexyl ester

To a stirred solution of 25.0 g (0.25 mol ) of cyclohexanol (purchasedfrom the Aldrich Chemical Company and used without purification) and27.3 g (0.27 mol ) of triethylamine in 500 mL of ether at -15° C. wasadded 28.6 g (0.25 mol ) of methanesulfonyl chloride in 50 mL of etherdropwise over 35 min. The reaction was warmed to 0° C. and stirred for 1h when the mixture was diluted water and washed with aqueous solutionsof 1N HCl and brine. The organics were dried (MgSO₄) and concentratedunder reduced pressure to provide 43.0 g, 96% yield of title mesylate asa colorless oil. The mesylate was used without further purification.

B. (Diethoxyphosphinyl)methanesulfonic acid, cyclohexyl ester

To a rapidly stirred, nitrogen-purged solution of 24.4 g (137 mmol) ofPart A mesylate in 600 mL of THF under nitrogen at -78° C. was added 55mL (137.5 mmol, 2.5M in hexanes) of n-butyl-lithium over 35 min. Thetemperature was not allowed to rise above -70° C. After an additional 10min, 11.8 g (68.5 mmol) of freshly distilled diethyl chlorophosphate wasadded to the resulting slightly turbid solution at a rate to keep thetemperature below -70° C. The reaction mixture was stirred for 45 minand then a solution of 8.30 g (138 mmol) of glacial acetic acid in 25 mLof THF was added over 5 minutes. The reaction mass was warmed to roomtemperature and evaporated at 30° C. at reduced pressure. The residuewas partitioned between 250 mL of dichloromethane and 75 mL of water andextracted twice with dichloromethane. The extracts were combined, driedover MgSO₄ and evaporated. The crude product was purified by flashchromatography (8×50 cm column, 2 L of dichloromethane, then 4 L of11:89 ether/dichloromethane, then 2 L of 1:4 ether/dichloromethane) togive title compound as a colorless oil, 11.4 g, 53%.

TLC Silica gel, (11:89 ether/dichloromethane) R_(f) =0.20.

¹ H NMR (CDCl₃, 400 MHz) δ4.83 (m, 1H) 4.26 (m, 4H) 3.72 (d, 2H, J=7.1Hz) 2.01 (m, 2H) 1.80-1.30 (m, 8H) 1.39 (t, 6H, J=7.3 Hz) ppm.

C.(E,E)-1-(Diethoxyphosphinyl)-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, cyclohexyl ester

To a suspension of 0.57 g (23.7 mmol, 1.9 eq.) of NaH in 50 mL of dryDMF at -20° C. under argon was added 9.00 g (28.7 mmol, 2.3 eq.) of PartB sulfonate over 15 min. to give a yellow solution. The reaction wasallowed to warm to room temperature and stir for 0.5 h when 4.48 g(12.46 mmol, 1 eq.) of Example 1 Part C iodide was added in one portion.The reaction mixture was stirred for 12 h when it was quenched with 100mL of saturated NaCl solution and diluted with 250 mL of ether. Thelayers were separated, the organics dried (Na₂ SO₄) and evaporated toprovide a crude oil. Flash chromatography was performed on 500 g ofsilica gel eluting with 3:7 ethyl acetate/hexane to provide 5.20 g (76%)of title compound in the form of a pale yellow oil.

TLC Silica gel (1:1 ethyl acetate/hexanes) R_(f) =0.60.

IR (film) 2934, 2861, 1449, 1352, 1260, 1173, 1053, 1024, 930 cm⁻¹.

¹ H NMR (CDCl₃, 270 MHz) δ5.05 (m, 3H) 4.75 (m, 1H) 4.15 (m, 4H) 3.40(dt, 1H, J=19.3, 6.4 Hz) 2.10-1.80 (m, 14H) 1.65-1.25 (m, 6H) 1.60 (s,3H) 1.53 (s, 9H) 1.30 (t, 6H, J=7.3 Hz) ppm.

Mass Spec. (CI, + ions) m/e 564 (M+NH₄), 547 (M+H), 482 (M+NH₄ -C₆ H₁₀),465 (M+H-C₆ H₁₀).

D. (E,E)-6,10,14-Trimethyl-1-phosphono-5,9,13-pentadecatriene-1-sulfonicacid, trisodium salt

To a solution of 1.00 g (1.82 mmol) of Part C compound and 20 mL ofmethanol in a sealable tube at 0° C. was added NH₃ (g) until thesolution was saturated. The tube was sealed and placed in an oil bath at75° C. for 16 h, at which point the tube was opened and the volatilesremoved under reduced pressure. The remainder was dissolved in drytoluene and evaporated two times (2×7.0 mL) leaving an amber oil. Theoil was dissolved in 10 mL of dry methylene chloride and treated with2.40 mL (9.0 mmol) of bis(trimethylsilyl)trifluoroacetamide (BSTFA) for0.5 h, followed by 0.79 mL (6.0 mmol) of bromotrimethylsilane. Thereaction mixture was stirred for 18 h when the solvent was evaporatedand the residue pumped (≈0.5 mm pressure) for 0.5 h. The remainder wasdissolved by adding 50 mL (10 mmol) of 0.2M NaOH solution and stirringvigorously for ten min. The soapy solution was freeze dried to provide awhite solid. The solid was purified by MPLC on a column of CHP20P gel(0.30 L) eluting with water (0.5 L) followed by isocratic elution with15% acetonitrile in water. Approximately 25 mL fractions were collected.Pure fractions were pooled and the aqueous solution lyophilized toprovide 0.80 g (91%) of title salt as a white lyophilate. The lyophilatewas diluted with 0.6 mL of water and the mixture mashed to a gummy whitesolid. The solid was repeatedly washed and mashed with acetone (3×4 mL)until a granular solid resulted. The granular solid was dried undervacuum for 10 h and collected to yield 0.75 g (85%) of title salt as afine white powder.

TLC Silica gel (6:3:1 n-propanol/conc. ammonia/water) R_(f) =0.35.

IR (KBr) 3434, 2924, 2857, 1667, 1449, 1209, 1136, 1109, 976 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ5.35 (t, 1H, J=7.0 Hz) 5.23 (q, 2H, J=7.0 Hz)2.93 (ddd, 1H, J=18.2, 7.0, 4.7 Hz) 2.20-1.80 (m, 12H) 1.74 (s, 3H) 1.65(s, 3H) 1.60 (s, 6H) 1.63 (m, 2H) ppm.

Mass Spec (FAB, + ions) m/e 497 (M+Na), 475 (M+H).

Anal. Calc'd for C₁₈ H₃₀ O₆ Na₃ PS+0.81 H₂ O: C, 44.20; H, 6.52; P,6.33; S, 6.55 Found: C, 43.83; H, 6.93; P, 6.02; S, 6.69.

EXAMPLE 1B

(E,E)-6,10,14-Trimethyl-1-phosphono-5,9,13-pentadecatriene-1-sulfonicacid, tripotassium salt

To a solution of 11.11 g (20.3 mmol) of Example 1A, Part C compound and120 mL of methanol in a sealable tube at 0° C. was added NH₃ (g) untilthe solution was saturated. The tube was sealed and placed in an oilbath at 65° C. for 24 h, at which point the tube was opened and thevolatiles removed under reduced pressure. The remainder was dissolved ina 1:1 mixture of dry toluene/hexamethyl disilazane (HMDS) and evaporatedtwo times (2×60 mL), leaving an amber oil. The oil was dissolved in 70mL of dry methylene chloride and treated with 21.4 mL (101.6 mmol) ofHMDS for 0.5 h at RT. The mixture was then treated with 16.0 mL (121.9mmol) of bromotrimethylsilane. The reaction was allowed to stir at RTfor 45 h when the solvent was evaporated and the residue pumped (≈0.5 mmpressure, 35° C.) for 0.5 h. The remainder was dissolved by adding 120mL (120 mmol) of 1M KOH solution and stirring vigorously for ten min.The soapy solution was freeze dried to provide a white solid. The solidwas purified by MPLC on a column of CHP20P gel (1 L ) eluting with water(2 L) followed by a stepwise gradient created by the addition of: 1:9acetonitrile/water (1.5 L), 1.5:8.5 acetonitrile/water (1.5 L), 2:8acetonitrile/water (1 L) and finally 2.5:7.5 acetonitrile/water (1 L).Approximately 50 mL fractions were collected. Fractions 52 to 83 werepooled, the acetonitrile was removed under reduced pressure and theaqueous solution lyophilized to provide 8.11 g (78%) of title compoundas a white lyophilate which was 98.5% pure by HPLC. The lyophilate wasdissolved with 16 mL of water, and 40 mg (0.5 mol %) of Trolox wasadded. The product was precipitated with 16 mL acetone, and theprecipitate was repeatedly washed (2×8 mL) and mashed with acetone untila solid resulted. The solid was dried under vacuum for 24 h andcollected to yield 7.58 g (72%) of title compound as a fine whitepowder.

TLC Silica gel (6:3:1 n-propanol/conc. ammonia/water) R_(f) =0.35.

IR (KBr) 3435, 2924, 2857, 1632, 1449, 1204, 1140, 1109, 974 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ5.15 (t, 1H, J=7.0 Hz) 5.06 (q, 2H, J=7.0 Hz)2.77 (ddd, 1H, J=18.2, 7.0, 4.7 Hz) 2.10-1.80 (m, 12H) 1.54 (s, 3H) 1.50(m, 2H) 1.49 (s, 3H 1.47 (s, 6H) ppm.

Mass Spec (FAB, + ions) m/e 561 (M+K), 523 (M+H), 485 (M-K+2H).

Anal. Calc'd for C₁₈ H₃₀ O₆ K₃ PS+0.59 H₂ O: C, 40.53; H, 5.89; P, 5.81;S, 6.13 Found: C, 40.50; H, 6.20; P, 5.67; S, 5.91.

EXAMPLE 2

(E)-6,10-Dimethyl-1-phosphono-5,9-undecadiene-1-sulfonic acid, trisodiumsalt

A. (E)-8-Chloro-2,6-dimethyl-2,6-octadiene

To a stirred solution of 30.0 g (0.194 mol) of(E)-3,7-dimethyl-2,6-octadien-1-ol and 28.27 mL (0.213 mol) of2,4,6-collidine under argon at room temperature was added dropwise 8.23g (0.194 mol) of lithium chloride in 100 mL of DMF. The mixture wascooled to 0° C. and treated with 16.56 mL (0.213 mol) of methanesulfonylchloride dropwise over 10 minutes. The reaction was stirred at 0° C. for1.5 hours (solid present), then was poured into 500 mL of ice/water. Theaqueous solution was washed three times with 200 mL portions of hexane,the organic layers were combined and washed with 5% KHSO₄, water,NaHCO₃, brine, dried (MgSO₄) and evaporated to provide 29.95 g of a paleyellow oil. Rapid flash chromatography was performed on 400 g of silicagel, eluting with 3:9 EtOAc/hexane. Pure product fractions were combinedand evaporated to provide 25.20 g (75%) of title compound as a paleyellow oil.

TLC Silica gel (8:1 hexane/EtOAc) R_(f) =0.68.

¹ H-NMR (CDCl₃, 270 MHz): δ5.44 (m, 1H), 5.08 (m, 1H), 4.09 (d, 2H,J=8.2 Hz), 2.08 (m, 4H), 1.73 (s, 3H), 1.68 (s, 3H), 1.60 (s, 3H) ppm.

B. (E)-(3,7-Dimethyl-2,6-octadienyl)propanedioic acid, diethyl ester

To a stirred solution of 14.68 g (0.611 mol) of NaH (100%) in 400 mL ofTHF at 0° C. under argon was added dropwise 92.76 mL (0.611 mol) ofdiethyl malonate in 100 mL of THF over 0.5 hours. This solution wasstirred for 0.5 hours at 0° C., at which time 35.20 g (0.204 mol) ofPart A chloride in 50 mL of THF was added dropwise over 15 minutes. Thereaction gradually warmed to room temperature, stirred for 18 hours thenwas quenched with 250 mL of saturated NH₄ Cl and diluted with 250 mL ofether. The organic layer was washed with water, brine, dried (MgSO₄) andevaporated to remove solvent and provide 100 g of an oil. The excessdiethyl malonate was removed by distillation at 75° C. (1.5 mm) toprovide 65 g of title compound also containing some dialkylated productand diethyl malonate.

TLC Silica gel (1:1 Hexane/Ethyl acetate) R_(f) =0.37.

IR (CCl₄) 2982, 2926, 2854, 1751, 1734, 1446, 1369, 1332, 1269, 1236,1209, 1149, 1111, 1095, 1035, 860 cm⁻¹.

¹ H NMR (CDCl₃, 270 MHz): δ5.07 (q, 2H, J=7.1 Hz), 4.18 (q, 2H, J=7.0Hz), 3.33 (t, 1H, J=7.6 Hz), 2.60 (t, 2H, J=7.3 Hz), 2.04-1.98 (m, 4H),1.68 (s, 3H), 1.64 (s, 3H), 1.59 (s, 3H), 1.26 (t, 6H, J=7.0 Hz) ppm.

MS (CI--NH₃, + ions) m/e 314 (M+NH₄), 297 (M+H).

C. (E)-5,9-Dimethyl-4,8-decadienoic acid, ethyl ester

To a solution of 65 g of the crude Part B diester described above, 5.40mL (0.30 mol) of water and 25.0 g (0.60 mol) of lithium chloride in 250mL of DMSO was heated to 190° C. and stirred for 9 hours. The reactionwas treated with a 1:1 solution of hexane/ether and then washed withwater and brine. The organic layer was dried (MgSO₄) and evaporated toprovide 34.6 g of title compound in the form of a yellow oil. No furtherpurification was performed; the sample was carried on to the next step.

TLC Silica gel (95:5 Hexane/Ethyl acetate) R_(f) =0.30.

¹ H NMR (CDCl₃, 270 MHz): δ5.00 (m, 2H), 4.04 (q, 2H, J=7.0 Hz), 2.23(m, 4H), 1.99-1.87 (m, 4H), 1.59 (s, 3H), 1.54 (s, 3H), 1.51 (s, 3H),1.17 3H, J=7.0 Hz) ppm.

MS (CI--NH₃, + ions) m/e 242 (M+NH₄), 225 (M+H).

D. (E)-5,9-Dimethyl-4,8-decadien-1-ol

To a stirred solution of 5.84 g (0.154 mol) of lithium aluminum hydridein 700 mL of ether at 0° C. under argon was added dropwise 34.50 g ofcrude Part C ester over 20 minutes. The mixture was stirred for 1.5hours at which time it was quenched by the following: 5.8 mL (0.324 mol)of water, 5.8 mL of 15% NaOH in water and then 17.5 mL (0.973 mol) ofwater. The granular mixture was stirred and dried (MgSO₄) for 0.5 hoursat which time the mixture was filtered through a celite cake and washedwith ether followed by dichloromethane. The filtrate was evaporated toprovide 28.16 g of an oil that was distilled using a short-pathapparatus (bp 95°-96° C., 0.3 mm) to provide 20.5 g (55% overall fromPart A chloride) of title alcohol as a colorless oil.

TLC Silica gel (Dichloromethane) R_(f) =0.11.

IR (CCl₄) 3620, 3340, 2966, 2924, 2877, 2856, 2729, 1670, 1446, 1377,1350, 1278, 1199, 1155, 1107, 1057, 985, 829, 814, 792 cm⁻¹.

¹ H NMR (CDCl₃, 270 MHz): δ5.10 (m, 2H), 3.62 (t, 2H, J=6.5 Hz),2.11-1.94 (m, 7H), 1.67-1.58 (m, 2H), 1.67 (s, 3H), 1.61 (s, 6H) ppm.

MS (CI--NH₃, + ions) m/e 200 (M+NH₄), 183 (M+H).

E. (E)-5,9-Dimethyl-4,8-decadien-1-ol, methanesulfonate ester

To a stirred solution of 12.0 g (65.93 mmol) of Part D alcohol in 200 mLof dichloromethane at 0° C. under argon was added 11.95 mL (85.71 mmol)of triethylamine and 6.12 mL (79.12 mmol) of methanesulfonyl chloride.The reaction was stirred for 1 hour then was diluted with ether andwashed with 5% KHSO₄, saturated NaHCO₃ and brine. The organic layer wasdried (MgSO₄) and evaporated to provide 16.91 g (98%) of title compoundas a pale yellow oil.

TLC Silica gel (Dichloromethane) R_(f) =0.53.

IR (CCl₄) 2963, 2927, 2922, 2882, 2875, 2856, 1455, 1450, 1381, 1363,1347, 1178, 1007, 969, 957, 929, 793, 785, 758 cm⁻¹.

¹ H NMR (CDCl₃, 270 MHz): δ5.09 (m, 2H), 4.21 (t, 2H, J=6.5 Hz), 2.98(s, 3H), 2.13-1.99 (m, 6H), 1.79 (quint., 2H, J=6.7 Hz), 1.68 (s,3H),1.61 (s, 3H), 1.60 (s, 3H)ppm.

MS (CI--NH₃, + ions ) m/e 278 (M+NH₄).

F. (E)-5,9-Dimethyl-4,8-decadien-1-yl iodide

To a stirred solution of 16.91 g (65.04 mmol) of Part E methanesulfonatein 500 mL of acetone at room temperature under argon was added 39.00 g(260.16 mmol) of sodium iodide. The reaction mixture was refluxed for3.5 hours, then diluted with 400 mL of a 1:1 mixture of water/hexane.The organic layer was washed with saturated sodium sulfite, dried(MgSO₄) and evaporated to provide 17.57 g of a pale yellow oil. The oilresidue was filtered through 400 g of silica gel eluting with hexane.The pure product fractions were combined and evaporated to provide 16.86g (89%) of title iodide as a colorless oil.

TLC Silica gel (Hexane) R_(f) =0.37.

IR (CCl₄) 2962, 2924, 2852, 1444, 1375, 1342, 1261, 1226, 1201, 1163,1107, 983, 873, 835, 819, 761, 742 cm⁻¹.

¹ H NMR (CDCl₃, 270 MHz): δ5.07 (t, 2H, J=7.0 Hz), 3.18 (t, 2H, J=7.0Hz), 2.14-1.96 (m, 6H), 1.86 (quint., 2H, J=7.0 Hz), 1.68 (s, 3H), 1.63(s, 3H), 1.60 (s, 3H)ppm.

G. (E)-1-(Diethyoxyphosphinyl)-5,9-undecadiene-1-sulfonic acid, sodiumsalt

To a suspension of 153 mg (6.40 mmol) of NaH in 10 mL of dry DMF at 0°C. under argon was added 1.66 g (6.40 mmol) of Example 1 Part Dsulfonate over 15 min. to give a yellow solution. The reaction wasallowed to warm to room temperature and stir for 0.5 h when 0.75 g (2.56mmol) of Part F iodide was added in one portion. The reaction mixturewas stirred for 18 h when it was quenched with 15 mL of saturated aq NH₄Cl solution and diluted with 100 ml of ethyl acetate. The fractions wereseparated and the organic layer washed with brine, dried (Na₂ SO₄) andevaporated to provide a crude glass. The glass was diluted with 2.5 ml(2.5 mmol) of 1M NaOH solution and purified by MPLC on a column ofCHP20P gel (2.5 cm diam. ×15 cm height) eluting with water (150 mL)followed by a gradient created by the gradual addition of 400 mL ofacetonitrile to a reservoir of 250 mL of water. Approximately 10 mLfractions were collected. The acetonitrile was removed under reducedpressure and the aqueous solution was lyophilized to provide 0.63 g(59%) of title salt as a white lyophilate.

TLC Silica gel (8:1:1 propanol/conc. NH₃ /water) R_(f) =0.65.

IR (film) 3468, 2972, 2926, 1664, 1444, 1376, 1241, 1036, 968, 812 cm⁻¹.

¹ H NMR (CD₃ OD, 270 MHz) δ5.10 (t, 1H, J=6.9 Hz) 5.05 (t, 1H, J=6.0 Hz)4.10 (m, 4H) 3.15 (dt, 1H, J=20.0, 6.5 Hz) 2.10-1.80 (m, 8H) 1.67 (m,2H) 1.60 (s, 3H) 1.55 (s, 3H) 1.53 (s, 3H) 1.25 (t, 6H, J=7.1 Hz) ppm.

H. (E) -6,10-Dimethyl-1-phosphono-5,9-undecadiene-1-sulfonic acid,trisodium salt

To a stirred solution of 0.63 g (1.50 mmol) of Part G salt in 8 mL ofdichloromethane at RT was added 0.36 g (3.00 mmol) of 2,4,6-collidinefollowed by 1.14 g (7.50 mmol) of bromotrimethylsilane. The reaction wasallowed to stir at RT for 14 h when the solvent was evaporated and thesemisolid residue pumped (≈1 mm pressure) for 0.5 h. The residue wasdissolved by adding 7.0 mL of 1M NaOH solution (7.0 mmol), then dilutingwith 15 mL of water. The solution was freeze dried to provide off whitesolids. The solids were purified by MPLC on a column of CHP20P gel (2.5cm diam. ×15 cm height) eluting with water (150 mL) followed by agradient created by the gradual addition of 400 mL of acetonitrile to areservoir of 250 mL of Water. Approximately 10 mL fractions werecollected. The acetonitrile was removed under reduced pressure and theaqueous solution was lyophilized to provide 0.40 g (65%) of titlecompound as a white lyophilate.

TLC Silica gel (5:4:1 n-propanol/conc. ammonia/water) R_(f) =0.45.

IR (KBr) 3425, 2964, 2926, 2858, 1641, 1450, 1203, 1099, 1053, 974 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ5.15 (t, 1H, J=7.0 Hz) 5.06 (t, 1H, J=7.0 Hz)2.77 (ddd, 1H, J=18.7, 6.7, 4.4 Hz) 2.10-1.80 (m, 8H) 1.55 (s, 3H) 1.50(m, 2H) 1.49 (s, 3H) 1.48 (s, 3H) ppm.

Mass Spec (FAB, + ions) m/e 429 (M+Na), 407 (M+H), 385 (M-Na+2H).

Anal. Calc'd for C₁₃ H₂₂ O₆ Na₃ PS+1.58 H₂ O: C, 35.92; H, 5.83; P,7.13; S, 7.38 Found: C, 35.92; H, 5.99; P, 7.24; S, 7.28.

EXAMPLE 3

α-Phosphono-[1,1'-Biphenyl]-4-butanesulfonic acid, trisodium salt

A. [1,1'-Biphenyl]-4-propanoic acid, 1,1-dimethylehtyl ester

To a stirred solution of 2.07 mL (14.80 mmol) of diisopropylamine in 15mL of THF was added 6.2 mL (9.87 mmol) of 1.6M butyllithium in hexanesto give a pale yellow solution. The solution was warmed to 0° C. for 15min and then cooled to -78° C. when 1.33 mL (9.87 mmol) of t-butylacetate was added neat over 10 min. After 15 min, 3.5 mL (20.2 mmol) ofHMPA was added and then 2.0 g (9.87 mmol) of 4-chloromethyl[1,1'-biphenyl] (Aldrich) was added in 20 mL of THF over 10 min. After 2h at -78° C., the reaction was diluted with ether and quenched withsaturated NH₄ Cl. The organic layer was washed with water and brine,dried (MgSO₄) and evaporated to provide 3.8 g of a clear oil. The crudeproduct was filtered through a pad of silica gel eluting with 500 mLeach of pentane, CH₂ Cl₂ and EtOAc. The latter two filtrates werecombined and evaporated to provide 1.97 g of an oil. Furtherpurification by flash chromatography on 200 g of silica gel packed in3:1 pentane/CH₂ Cl₂ and eluted with 2:1 pentane/CH₂ Cl₂ gave 1.27 g(45%) of title ester as a clear, colorless oil.

IR (CCl₄) 2980, 2932, 1732, 1487, 1368, 1148, 698 cm⁻¹.

¹ H NMR (CDCl₃, 270 MHz): δ7.50, 7.56 (two din, 2H each J=7 Hz) 7.42(tm, 2H, J=7 Hz) 7.20-7.40 (m, 3H, H₃, H₉) 2.94 (t, 2H, J=7.6 Hz) 2.58(t, 2H, J=7.6 Hz) 1.43 (s, 9H) ppm.

MS (CI--NH₃, + ions) m/z 300 (M+NH₄), 283 (M+H).

Anal. Calc'd for C₁₉ H₂₂ O₂ : C, 80.81; H, 7.85 Found: C, 81.10; H,7.88.

B. 4-(3-Hydroxypropyl) [1,1'-biphenyl]

To a suspension of 250 mg (6.58 mmol) of LAH in 15 mL of ether at 0° C.under argon was added 1.24 g (4.39 mmol) of Part A ester in 20 mL ofether over 10 min. After 0.5 h at 0° C., the reaction was carefullyquenched by the sequential addition of 0.26 mL of water, 0.26 mL of 15%NaOH, and 0.79 mL of water. The mixture was stirred for 0.5 h, Na₂ SO₄was added and after an additional 1 h of stirring, the solids wereremoved by filtration through a pad of Celite. The solids were washedwith ether, the filtrate was evaporated and the residue was purified byflash chromatography on 90 g of silica gel eluted with CH₂ Cl₂ toprovide 857 mg (92%) of title alcohol as a white solid, mp 72°-74° C.

IR (CCl₄) 3639, 3550 (br) 3029, 2939, 2875, 1602, 1487, 1041, 698 cm⁻¹.

¹ H NMR (CDCl₃, 270 MHz): δ7.50, 7.55 (two dm, 2H each, J=7 Hz) 7.40(tm, 2H, J=7 Hz) 7.29 (tm, 1H, J=7 Hz) 7.24 (d, 2H, J=7.6 Hz) 3.68 (t,2H, J=6.3 Hz) 2.72 (t, 2H, J=7.6 Hz) 1.90 (tt, 2H, J=6.3, 7.6 Hz) 1.83(br s, 1H, OH) ppm.

MS (CI--NH₃, + ions) m/z 230 (M+NH₄), 212 (M+H).

Anal. Calc'd for C₁₅ H₁₆ O: C, 84.87; H, 7.60 Found: C, 84.95; H, 7.67.

C. 4-(3-Iodopropyl) [1.1'-biphenyl]

To a stirred solution of 857 mg (4.04 mmol) of Part B alcohol, 1.16 g(4.44 mmol) of triphenylphosphine and 577 mg (8.48 mmol) of imidazole in30 mL of dry THF under argon at room temperature was added 1.13 g (4.44mmol) of iodine in 25 mL of THF dropwise over 40 min. After 1 h, thereaction was diluted with ether and washed with water, saturated Na₂ S₂O₃ and brine, dried (MgSO₄) and evaporated to provide an oily, whitesolid. Flash chromatography on 65 g of silica gel eluted with CH₂ Cl₂provided 806 mg (62%) of title iodide as a white solid, mp 42°-43° C.

¹ H NMR (CDCl₃, 270 MHz): δ7.50, 7.55 (two dm, 2H each, J=7 Hz) 7.41(tm, 2H, J=7 Hz) 7.31 (tm, 1H, J=7 Hz) 7.25 (d, 2H, J=7.6 Hz) 3.18 (t,2H, J=7 Hz) 2.75 (t, 2H, J=7 Hz) 2.14 (quint, 2H, J=7 Hz) ppm.

MS (CI--NH₃, + ions) m/z 340 (M+NH₄), 322 (M+H).

Anal. Calc'd for C₁₅ H₁₅ I: C, 55.92; H, 4.69; I, 39.39 Found: C, 56.04;H, 4.70; I, 39.37.

D. (E,E)-1-(Diethoxyphosphinyl)-[1,1,'-biphenyl]-4-butanesulfonic acid,sodium salt

To a suspension of 223 mg (9.30 mmol) of NaH in 7 mL of dry DMF at 0° C.under argon was added 2.41 g (9.30 mmol) of Example 1 Part D sulfonateover 15 min. to give a yellow solution. The reaction was allowed to warmto room temperature and stir for 0.5 h when 1.00 g (3.10 mmol) of Part Ciodide was added in 3 mL of DMF over 2 min. The reaction mixture wasstirred for 18 h when it was quenched with 10 mL of saturated aq NaClsolution and diluted with 100 ml of ethyl acetate. The fractions wereseparated and the organic layer washed with brine, dried (Na₂ SO₄) andevaporated to provide a crude glass. The glass was diluted with 2.5 mlof 1M NaOH solution and purified by MPLC on a column of CHP20P gel (2.5cm diam. ×15 cm height) eluting with water (150 mL) followed by agradient created by the gradual addition of 400 mL of acetonitrile to areservoir of 250 mL of water. Approximately 10 mL fractions werecollected. The acetonitrile was removed under reduced pressure and theaqueous solution was lyophilized to provide 1.10 g (79%) of title saltas a viscous glass.

TLC Silica gel (7:2:1 propanol/conc. NH₃ /water) R_(f) =0.55.

IR (film) 3466, 2984, 2932, 1614, 1485, 1444, 1392, 1368, 1240, 1069,1035, 970, 794 cm⁻¹.

¹ H NMR (CDCl₃, 270 MHz) δ7.40-7.10 (m 9H) 4.10 (m, 4H) 3.15 (m, 1H)2.65 (m, 2H) 2.30 (m, 1H) 2.00 (m, 3H) 1.25 (t, 6H, J=7.1 Hz)ppm.

Mass Spec (FAB, + ions) m/e 471 (M+Na), 449 (M+H).

E. α-Phosphono-[1,1'-biphenyl]-4-butanesulfonic acid, trisodium salt

To a stirred solution of 1.10 g (2.45 mmol) of Part D salt in 8 mL ofdichloromethane at RT was added 1.49 g (9.80 mmol) ofbromotrimethylsilane. The reaction was allowed to stir at RT for 14 hwhen the solvent was evaporated and the semisolid residue pumped (≈1 mmpressure) for 0.5 h. The residue was dissolved by adding 10 mL of 1MNaOH solution (10 mmol). The solution was purified by MPLC on a columnof CHP20P gel (2.5 cm diam. ×15 cm height) eluting with water (150 mL)followed by a gradient created by the gradual addition of 400 mL ofacetonitrile to a reservoir of 250 mL of water. Approximately 10 mLfractions were collected. Pure fractions were combined and theacetonitrile was removed under reduced pressure. The aqueous solutionwas lyophilized to provide 0.27 g (25%) of title salt as a whitelyophilate.

TLC Silica gel (5:4:1 n-propanol/conc. ammonia/water) R_(f) =0.45.

IR (KBr) 3433, 3029, 2931, 1636, 1487, 1450, 1202, 1094, 1053, 973 cm⁻¹.

¹ H NMR (D₂ O, 270 MHz) δ7.70, 7.55, 7.45 (3m, 9H) 2.97 (ddd, 1H,J=15.8, 6.5, 4.7 Hz) 2.75 (m, 2H) 2.00 (m, 4H)

Mass Spec (FAB, + ions) m/e 459 (M+Na), 437 (M+H), 415 (M-Na+2H).

Anal. Calc'd for C₁₆ H₁₆ O₆ Na₃ PS+2.00 H₂ O; C, 40.69; H, 4.27; P,6.56; S, 6.79 Found: C, 40.90; H, 4.39; P, 6.43; S, 6.89.

EXAMPLE 4

(E)-4-(4-Heptylphenyl)-1-phosphono-3-butene-1-sulfonic acid,tripotassium salt

A. 4-Heptylbenzaldehyde

To a stirred solution of 6.60 g (30 mmol) of 4-heptylbenzoic acid(obtained from Aldrich Chemical Company (#23,064-2) and used withoutpurification) in 50 mL of dichloromethane at room temperature undernitrogen was added 4.0 mL (45 mmol, 1.5 equivalents) of oxalyl chlorideand then 0.1 mL (1.3 mmol) of DMF. The resulting vigorously bubblingsolution was stirred for 1 h and then evaporated. The semi-solid residuewas dissolved in 40 mL of benzene under argon and 350 mg (0.31 mmol) oftetrakis(triphenylphosphine)palladium was added. To this stirringsolution at room temperature was added 11.1 mL (34 mmol) of tributyltinhydride over 20 min. The solution turns yellow and warms autogenously to40° C. After 1 h, the reaction was treated with 100 mL of 10% aqueouspotassium fluoride and stirred vigorously for 30 min. The reaction masswas filtered, the filtrate diluted with ether, washed with water, andthe organic layer separated, dried (MgSO₄) and evaporated onto 10 g ofsilica gel. Purification by flash chromatography (5×20 cm column, 3:7dichloromethane/hexanes as elutent) gave 5.95 g, 97% yield, of titlecompound as a colorless oil.

B. α-Ethenyl-4-heptylbenzenemethanol, acetate ester

To a stirred slurry of 42.0 mL (42.0 mmol, 1M in THF) of vinyl magnesiumbromide in 40 mL of THF at -40° C. under argon was added a solution of5.85 g (28.6 mmol) of Part A compound in 10 mL of THF over 20 min. Theresulting pale yellow solution was warmed to room temperature, stirredfor 2 h and then quenched with saturated ammonium chloride solution. Thereaction mixture was extracted twice with ether. The extracts werecombined, dried (MgSO₄) and evaporated. The resulting yellow oil wasdissolved in 50 mL of dichloromethane at room temperature under nitrogenand 5.6 mL (40 mmol) of triethylamine and 3.8 mL (40 mmol) of aceticanhydride were added, followed by 100 mg (0.4 mmol) of4-dimethylaminopyridine (DMAP). After 30 minutes, the reaction mixturewas diluted with ether, washed twice with 10% citric acid, once withbrine and once with saturated sodium bicarbonate. The organic phase wasdried, (MgSO₄) and evaporated onto 10 g of silica gel. Purification byflash chromatography (5×25 cm column, 35:65 dichloromethane/hexanes aselutent) gave 7.12 g, 91%, of title compound.

C. (E) -1-(Diethoxyphosphinyl)-4-(4-heptylphenyl)-3-butenesulfonic acid,1-methylethyl ester

To a stirred solution of 2.75 g (10.0 mmol) of Part B compound, 6.7 mL(27 mmol, 2.2 equiv.) of bis(trimethylsilyl)acetamide, 3.45 g (12.6mmol, 1.26 equiv.) of Example 1A, Part B sulfonate and 270 mg (1 mmol)of triphenyl-phosphine in 30 mL of THF under argon was added 600 mg(0.54 mmol) of tetrakis(triphenylphosphine)-palladium. The resultingmixture was heated to reflux for 1 hour. The reaction was cooled,evaporated, diluted with ether and washed once with 10% citric acid andthrice with water. The organic phase was dried (MgSO₄) and evaporated.Purification by flash chromatography on silica gel (5×20 cm column)eluted with 1:19 ether/dichloromethane gave title compound as acolorless oil, 3.10 g, 67% yield.

D. (E)-4-(4-Heptylphenyl)-1-phosphono-3-butene-1-sulfonic acid,tripotassium salt

To a stirred solution of 458 mg (1.0 mmol) of Part C compound, in 5 mLof dichloromethane under argon at room temperature was added 420 mL (2.0mmol) of bis(trimethylsilyl)trifluoroacetamide and then 530 mL (4.0mmol) of bromotrimethylsilane. After 16 h, the resulting clear solutionwas evaporated at 25° C. and the residue dissolved in 5 mL of THF. Tothis stirred solution was added 200 mg (1.2 mmol) of dried, finelyground potassium iodide and 5 mg (0.02 mmol) of 18-crown-6. Theresulting slurry was heated to reflux for 24 h, evaporated and thenstirred for 1 h with 6 mL (3 mmol) of 0.5M potassium hydroxide solution.The solution was lyophilized and then purified by MPLC (2.5×20 cm columnof Mitsubishi Kasei Sepadbeads HP-20 resin): 11.5 mL fractions, 7 mL/minflow rate, eluted with 200 mL of water and then a gradient prepared from400 mL of water and 450 mL of 2:1 acetonitrile/water). Fractions 23-25were collected and lyophilized to give title salt as a white solid, 485mg, 89% yield.

IR (KBr pellet) 3414, 2924, 2853, 1653, 1198, 1154, 1092, 972 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ23 (d, 2H, J=7.1 Hz) 7.06 (d, 2H, J=7.1 Hz)6.35 (m, 2H) 2.91 (dm, 1H, J=14.5 Hz) 2.79 (t, 1H, J=13.6 Hz) 2.64 (m,1H) 2.79 (t, 1H, J=13.6 Hz) 2.43 (t, 2H, J=6.6 Hz) 1.42 (m, 2H) 1.12 (m,8H) 0.68 (t, 3H, J=6.0 Hz) ppm.

Anal. Calc'd for C₁₇ H₂₄ K₃ O₆ PS.2.25 H₂ O: C, 37.45; H, 5.27; P, 5.68;S, 5.88 Found: C, 37.09; H, 5.43; P, 6.08; S, 6.12.

MS (FAB, + ions) m/e 543 (M+K), 505 (M+H), 423 (M-2K-3H).

EXAMPLE 5

α-Heptyl-α-phosphonobenzenebutanesulfonic acid, tripotassium salt

A. α-(Diethoxyphosphinyl)-4-heptylbenzenebutanesulfonic acid,1-methylethyl ester

To an argon-purged solution of 675 mg (1.38 mmol) of Example 4 Part Ccompound and 100 mg of 10% palladium-on-carbon in 20 mL of ethyl acetatein a 500 mL one-neck round bottom flask was attached a hydrogen-filledrubber bladder of approximately 1 L capacity. The reaction mixture wasvigorously stirred for 16 h, purged with nitrogen, filtered throughCelite and the filtrate evaporated. The oily residue was redissolved indichlormethane, filtered through a 0.75 m filter and re-evaporated togive title compound as a colorless oil, 640 mg, 94% yield. The productwas used without further purification.

B. 4-Heptyl-α-phosphonobenzenebutanesulfonic acid, tripotassium salt

To a stirred solution of 620 mg (1.26 mmol) of Part A compound in 5 mLof dichloromethane under argon at room temperature was added 660 mL (5mmol) of bromotrimethylsilane. After 24 h, the resulting clear solutionwas evaporated at 25° C. and the residue dissolved in 5 mL of THF. Tothis stirred solution was added 225 mg (1.4 mmol) of dried, finelyground potassium iodide and 3 mg (0.01 mmol) of 18-crown-6. Theresulting slurry was heated to reflux for 24 h, evaporated and thenstirred for 1 h with 4 mL (4 mmol) of 1.0M potassium hydroxide solution.The solution was lyophilized and then purified by MPLC (2.5×20 cm columnof Mitsubishi Kasei Sepadbeads HP-20 resin): 11.5 mL fractions, 7 mL/minflow rate, eluted with 200 mL of water and then a gradient prepared from400 mL of water and 450 mL of 2:1 acetonitrile/water). Fractions 36-41were collected and lyophilized to give title compound as a white solid,550 mg, 84% yield.

IR (KBr pellet) 3434, 2926, 2855, 1649, 1460, 1200, 1084, 1049, 966cm⁻¹.

¹ H NMR (D₂ O, 270 MHz) δ7.08 (d, 2H, J=7.6 Hz) 7.02 (d, 2H, J=7.6 Hz)2.81 (dm, 1H, J=17 Hz) 2.47 (m, 2H) 2.41 (t, 2H, J=7.9 Hz) 1.78 (m, 4H)1.41 (m, 2H) 0.69 (t, 3H, J=6.4 Hz) ppm.

Anal. Calc'd for C₁₇ H₂₆ K₃ O₆ PS.0.75 H₂ O: C, 39.25: H, 5.33; P, 5.95;S, 6.16 Found: C, 39.45; H, 5.72; P, 5.71; S, 5.83.

MS (FAB, + ions) m/e 545 (M+K), 507 (M+H), 469 (M-K+2H).

EXAMPLE 6

(E) -4-(4'-Propyl[1,1'-biphenyl]-4-yl)-1-phosphono-3-butene-1-sulfonicacid, tripotassium salt

A. (E)-(4'-Propyl[1,1'-biphenyl]-4-yl)-2-propen-1-ol. acetate ester

A(1). (E)-(4'-Propyl[1,1'-biphenyl]-4-yl)-2-propenoic acid, n-butylester

A stirred solution of 4.13 g (15 mmol) of 4-bromo-4'-n-propylbiphenyl,106 mg (0.35 mmol) of tri-p-tolylphosphine, 2.7 mL (19 mmol) of n-butylacrylate, 7.4 mL (30.8 mmol) of tributylamine and 10 mg (0.1 mmol) ofhydroquinone was purged with a stream of nitrogen gas for 20 min at roomtemperature. To this mixture was added 4 mg (0.018 mmol) of palladiumacetate. The reaction was heated to 150° C. for 18 h under argon andthen cooled to room temperature. The resulting slurry was diluted withether, extracted twice with 50 mL of 1M hydrochloric acid, once withbrine and once with saturated sodium bicarbonate solution. The organicphase was dried (MgSO₄) and evaporated. The Crude product (4.5 g) waspurified by flash chromatography on silica gel (5×25 cm column) elutedwith 1 L of hexanes and then 1:1 dichloromethane/hexanes to give 4.08 g(81%) of title ester as a colorless oil.

A(2). (E)-(4'-propyl[1,1'-biphenyl]-4-yl)-2-propen-1-ol, acetate ester

To a stirred solution of 3.22 g (10.0 mmol) of Part A(1) ester in 50 mLof dichloromethane at 0° C. under nitrogen was added a solution of 22 mL(22 mmol, 1M in hexanes) of diisobutylaluminum hydride over 5 min. Theresulting pale yellow solution was stirred for 2 h and then quenchedwith 2 mL of methanol. The solution was then treated with 150 mL of 1Mpotassium sodium tartrate. A gel formed which dissolved within 5 min.The reaction mixture was extracted twice with ether. The extracts werecombined, dried (Na₂ SO₄) and evaporated. The resulting oil (2.6 g) wasdissolved in 25 mL of THF, cooled to 0° C. under nitrogen and 4.6 mL (25mmol) of diisopropylethylamine and 2.4 mL (25 mmol) of acetic anhydridewas added. After 1 h, the reaction mixture was diluted with ether,washed twice with 1M hydrochloric acid once with brine and once withsaturated sodium bicarbonate. The organic phase was dried (MgSO₄) andevaporated onto 10 g of silica gel. Purification by flash chromatographyon silica gel (5×20 cm column) eluted with 9:11 dichloromethane:hexaneto give title compound as a colorless oil, 2.21 g, 88% from Part A(1)ester.

B.(E)-1-(Diethoxyphosphinyl)-4-(4'-propyl[1,1'-biphenyl]-4-yl)-3-butene-1-sulfonicacid, cyclohexyl ester

To a stirred solution of 1.91 g (6.50 mmol) of Part A compound, 2.5 mL(10 mmol, 1.5 equiv.) of bis(tri-methylsilyl)acetamide, 3.00 g (9.5mmol, 1.46 equiv.) of Example 1A, Part B sulfonate and 180 mg (0.7 mmol)of triphenylphosphine in 10 mL of THF under argon was added 400 mg (0.35mmol) of tetrakis (tri-phenylphosphino) palladium. The resulting mixturewas heated to reflux for 1 hour. The reaction was cooled, evaporated,diluted with ether and washed once with 10% citric acid and thrice withwater. The organic phase was dried (MgSO₄) and evaporated. Purificationby flash chromatography on silica gel (5×20 cm column) eluted with 3:97ether/dichloromethane gave title compound as a colorless oil, 2.32 g,65% yield.

C. (E)-4-(4'-Propyl[1,1'-biphenyl]-4-yl)-1-phosphono-3-butene-1-sulfonicacid, tripotassium salt

To a stirred solution of 578 mg (1.05 mmol) of Part B compound in 5 mLof dichloromethane under argon at room temperature was added 560 mL (2.1mmol) of bis(trimethylsilyl)trifluoroacetamide and then 560 mL (4.2mmol) of bromotrimethylsilane. After 72 h, the resulting clear solutionwas evaporated at 25° C. and the residue dissolved in 5 mL of THF. Tothis stirred solution was added 180 mg (1.1 mmol) of dried, finelyground potassium iodide and 3 mg (0.01 mmol) of 18-crown-6. Theresulting slurry was heated to reflux for 20 h, evaporated and thenstirred for 1 h with 8 mL (4 mmol) of 0.5M potassium hydroxide solution.The solution was lyophilized and then purified by MPLC (2.5×20 cm columnof Mitsubishi Kasei Sepadbeads SP-207SS resin): 11.5 mL fractions, 7mL/min flow rate, eluted with 200 mL of water and then a gradientprepared from 400 mL of water and 450 mL of 2:1 acetonitrile/water).Fractions 20-34 were collected and lyophilized to give title salt as awhite solid, 505 mg, 85% yield.

IR (KBr pellet) 3422, 2959, 2930, 2870, 1653, 1497, 1202, 1080, 968cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ7.45 (d, 2H, J=8.6 Hz) 7.43 (d, 2H, J=8.6 Hz)7.39 (d, 2H, J=8.1 Hz) 7.15 (d, 2H, J=8.1 Hz) 6.44 (m, 2H) 2.98 (dm, 1H,J=13.2 Hz) 2.87 (tm, 1H, J=13.6 Hz) 2.68 (m, 1H) 2.44 (t, 2H, J=6.0 Hz)1.46 (dq, 2H, J=6.0 Hz) 0.73 (t, 3H, J=6.0 Hz) ppm.

Anal. Calc'd for C₁₉ H₂₀ K₃ O₆ PS.2.2 H₂ O: C, 40.45; H, 4.36; P, 5.49;S, 5.68 Found: C, 40.11; H, 4.70; P, 5.18; S, 5.95.

MS (FAB, + ions) m/e 563 (M+K), 525 (M+H), 487 (M-K+2H).

EXAMPLE 7

α-Phosphono-4'-Propyl[1,1'-biphenyl]-4-butanesulfonic acid, triponassiumsalt

A. α-(Diethoxyphosphinyl)-4'-propyl[1,1'-biphenyl]-4-butanesulfonicacid, cyclohexyl ester

To a nitrogen-purged solution of 1.30 mg (2.37 mmol) of Example 6 Part Bcompound in 50 mL of ethyl acetate in a 500 mL one-neck round bottomflask was attached a hydrogen-filled rubber bladder of approximately 1 Lcapacity. The reaction mixture was vigorously stirred for 16 h, purgedwith nitrogen, filtered through Celite and the filtrate evaporated. Theoily residue was redissolved in dichlormethane, filtered through a 0.75μ (micron) filter and re-evaporated to give title compound as acolorless oil, 1.28 g, 98% yield. The product was used without furtherpurification.

B. α-Phosphono-4'-propyl[1,1'-biphenyl]-4-butanesulfonic acid,tripotassium salt

To a stirred solution of 1.14 g (2.06 mmol) of Part A compound in 10 mLof dichloromethane under argon at room temperature was added 1.10 mL(8.3 mmol) of bromotrimethylsilane. After 24 h, the resulting clearsolution was evaporated at 25° C. and the residue dissolved in 10 mL ofTHF. To this stirred solution was added 340 mg (2.1 mmol) of dried,finely ground potassium iodide and 5 mg (0.02 mmol) of 18-crown-6. Theresulting slurry was heated to reflux for 24 h, evaporated and thenstirred for 1 h with 8 mL (8 mmol) of 1.0M potassium hydroxide solution.The solution was lyophilized and then purified by MPLC (2.5×20 cm columnof Mitsubishi Kasei Sepadbeads SP207SS resin): 11.5 mL fractions, 7mL/min flow rate, eluted with 200 mL of water and then a gradientprepared from 400 mL of water and 450 mL of 1:1 acetonitrile/water).Fractions 27-31 were collected and lyophilized to give title compound asa white solid, 450 mg, 39% yield.

IR (KBr pellet) 3432, 2957, 2930, 2870, 1636, 1499, 1198, 1080, 1049,966 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ7.47 (d, 2H, J=7.5 Hz) 7.46 (d, 2H, J=7.3 Hz)7.28 (d, 2H, J=7.5 Hz) 7.21 (d, 2H, J=7.3 Hz) 2.86 (dm, 1H, J=18.4 Hz)2.58 (m, 2H) 2.49 (t, 2H, J=7.2 Hz) 1.85 (m, 4H) 1.50 (m, 2H) 0.78 (t,3H, J=6.0 Hz) ppm.

Anal. Calc'd for C₁₉ H₂₂ K₃ O₆ PS.1.9 H₂ O: C, 40.68; H, 4.64; P, 5.52;S, 5.72 Found: C, 40.69; H, 5.00; P, 5.46; S, 6.00.

MS (ion spray, + ions) m/e 495 (M-3K+4H+2CH₃ CN), 492 (M-2K+3H+CH₃ CN),489 (M-K+2H), 454 (M-3K+4H+CH₃ CN), 451 (M-2K+3H), 413 (M-3K+4H).

EXAMPLE 8

4-(2-Phenylethoxy)-α-phosphonobenzenebutanesulfonic acid, dipotassiumsalt

A. 4-(2-Phenylethoxy)benzenepropanoic acid, 2-phenylethyl ester

To a stirred solution of 5.00 g (30.1 mmol) of 4-hydroxybenzenepropanoicacid, 8.0 mL of 2-phenylethanol (67 mmol) and 16.3 g (61 mmol) oftriphenyl-phosphine in 50 mL of THF at -10° C. under argon was added asolution 12.0 mL (61 mmol) of diisopropyl diazodicarboxylate in 50 mL ofTHF over the course of 4 hours. The resulting light yellow solution wasallowed to warm to room temperature, stirred 16 h and then evaporated.The oily residue was triturated in 500 mL of hot hexane until aprecipitate formed. The solids were filtered off and treated with anadditional 100 mL of hot hexane. The filtrates were combined andconcentrated. Purification of the residue by flash chromatography (5×20cm column, 3:2 dichloromethane/hexanes as elutent) gave 6.51 g, 58%yield, of title compound as a colorless oil.

B. 1-(3-Iodopropyl)-4-(2-phenylethoxy)benzene

To a stirred solution of 6.20 g (16.6 mmol) of Part A compound in 50 mLof THF at room temperature under argon was added a 1M solution oflithium aluminum hydride (9.0 mL, 2.2 equivalents) in THF. After 2 h,the reaction was quenched with 1M sodium potassium tartrate solution andextracted twice with ether. The organic extracts were dried (MgSO₄) andevaporated.

The residue was stirred in 25 mL of dichloromethane at 0° C. under argonwith 2.8 mL (20 mmol) of triethyl amine. To this solution was added,over 20 min, 1.3 mL (17 mmol) of methanesulfonyl chloride. After anadditional 20 min, the reaction mixture was diluted with dichloromethaneand washed twice with 10% citric acid. The organic extracts were dried(MgSO₄) and evaporated.

The resulting yellow oil was stirred at reflux under argon in a solutionof 25 mL of acetone containing 3 g (20 mmol) of sodium iodide. After 16h, the reaction mixture was cooled and diluted with an iced solution of5% aqueous sodium bisulfite. After two extractions with hexane, theextracts were dried (MgSO₄) and evaporated. Purification on silica gel(5×20 cm column, 1:7 dichloromethane/hexanes as elutent) gave 4.13 g,68%, of Part B compound from Part A compound.

C. α-(Diethoxyphosphinyl)-4-(2-phenylethoxy) benzenebutanesulfonic acid,cyclohexyl ester

To a stirred slurry of 120 mg (3.0 mmol, 60% mineral oil dispersion) ofsodium hydride in 3 mL of DMF under argon at -20° C. was added asolution of 1.12 g (3.56 mmol, 1.3 equiv.) of Example 1A, Part Bsulfonate in 1 mL of DMF. After addition was complete, the reaction waswarmed to room temperature and stirred for 30 min. To the resultingsolution was added a solution of 1.00 g (2.73 mmol) of Part B compoundin 1 mL of DMF. The reaction was stirred for 16 h, diluted with etherand washed once with 10% citric acid and thrice with water. The organicphase was dried (MgSO₄) and evaporated. Purification by chromatographyon silica gel (5×20 cm column) eluted with 1:19 ether/dichloromethanegave title compound as a colorless oil, 935 mg, 62% yield.

D. 4-(2-Phenylethoxy)-α-phosphonobenzenebutanesulfonic acid, dipotassiumsalt

To a stirred solution of 648 mg (1.2 mmol) of Part C compound in 5 mL ofdichloromethane under argon at room temperature was added 620 mL (3.0mmol) of bis(trimethylsilyl)trifluoroacetamide and then 620 mL (6.9mmol) of bromotrimethylsilane. After 16 h, the resulting clear solutionwas evaporated at 25° C. and the residue dissolved in 6 mL of THF. Tothis stirred solution was added 250 mg (1.5 mmol) of dried, finelyground potassium iodide and 3 mg (0.01 mmol) of 18-crown-6. Theresulting slurry was heated to reflux for 24 h, evaporated and thenstirred for 1 h with 8 mL (4 mmol) of 0.5M potassium hydroxide solution.The solution was lyophilized and then purified by MPLC (2.5×20 cm columnof Mitsubishi Kasei Sepadbeads HP-20 resin): 11.5 mL fractions, 7 mL/minflow rate, eluted with 200 mL of water and then a gradient prepared from400 mL of water and 450 mL of 2:1 acetonitrile/water). Fractions 25-32were collected and lyophilized to give title salt as a white solid, 385mg, 57% yield.

IR (KBr pellet) 3434, 3088, 2936, 2868, 1636, 1512, 1198, 1076, 966cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ7.21 (m, 5H) 7.09 (d, 2H, J=8.6 Hz) 6.76 (d,2H, J=8.6 Hz) 4.15 (t, 2H, J=6.4 Hz) 2.91 (t, 2H, J=6.4 Hz) 2.77 (dm,1H, J=18.0 Hz) 2.44 (m, 2H) 1.67 (m, 2H) ppm.

Anal. Calc'd for C₁₈ H₂₁ K₂ O₇ PS.3.75 H₂ O: C, 38.73; H, 5.15; P, 5.55;S, 5.74 Found: C, 38.73; H, 5.10; P, 5.24; S, 5.51.

MS (FAB, + ions) m/e 567 (M+2K-H), 529 (M+K).

EXAMPLE 9

6-(Hexyloxy)-α-phosphono-2-naphthalenebutanesulfonic acid, dipotassiumsalt

A. 2-Bromo-6-(hexyloxy)naphthalene

To a stirred solution of 4.46 g (20.0 mmol) of 6-bromo-2-naphthalenol(obtained from Aldrich Chemical Company (#B7,340-6) and used withoutpurification), in 20 mL of DMF at room temperature under argon was added480 mg (20 mmol) of 95% sodium hydride over the course of 15 min. Theresulting light yellow solution was stirred 30 min and 3.5 mL (22 mmol)of 1-bromohexane was added. The reaction was heated to 50° C. andstirred for 60 min. The reaction was quenched with ice water, theresultings solids filtered, washed with water and dried in vacuo at 60°C. Purification of the residue by chromatography on silica gel (5×20 cmcolumn, hexanes as elutant) gave 5.00 g, 81% yield, of title compound asa colorless oil.

B. α-Ethenyl-6-(hexyloxy)-2-naphthalenemethanol

To a stirred solution of 2.23 g (7.25 mmol) of Part A compound in 25 mLof THF under argon at -78° C. was added a solution of 8.5 mL (14.5 mmol)of 1.7M t-butyllithium in pentane over 10 min. After 15 min, a yellowslurry had formed. This was warmed to 0° C. and the resulting organicsolution was stirred for 30 min. To this reaction mixture was added 550mL (9.5 mmol, 1.3 equivalents) of freshly distilled acrolein at a rateto keep the temperature below 5° C. After an additional 30 min, thereaction was quenched with saturated ammonium chloride solution,extracted twice with ether, dried (MgSO₄) and evaporated.Recrystallization from hexanes gave title compound as a white solid, mp47°-48° C., 1.83 g, 89%.

C. α-Ethenyl-6-(hexyloxy)-2-naphthalenemethanol, acetate ester

To a solution of 1.43 g (5.0 mmol) of Part B compound and 1.1 mL (8mmol) of triethylamine in 15 mL of CH₂ Cl₂ at room temperature underargon was added 0.7 mL (6.6 mmol) of acetic anhydride and 20 mg (0.16mmol) of 4-dimethylaminopyridine. After 10 min, the reaction mixture wasevaporated, diluted with ether, washed once with 10% citric acid, oncewith water, once with saturated sodium bicarbonate solution, dried(MgSO₄) and evaporated to give title compound as a colorless oil, 1.54g, 94%. The compound was used without further purification for thesubsequent reaction.

D.(E)-1-(Diethoxyphosphinyl)-4-[6-(hexyloxy)-2-naphthalenyl]-3-butenesulfonicacid, cyclohexyl ester

To a stirred solution of 1.47 g (4.5 mmol) of Part C compound, 1.55 mL(6.6 mmol, 1.5 equiv.) of bis(trimethylsilyl)acetamide, 1.85 g (5.85mmol, 1.3 equiv.) of Example 1A, Part B sulfonate and 125 mg (0.5 mmol)of triphenylphosine in 10 mL of THF under argon was added 270 mg (0.24mmol) of tetrakis(triphenylphosphine)palladium. The resulting mixturewas heated to reflux for 1 hour. The reaction was cooled, evaporated,diluted with ether and washed once with 10% citric acid and thrice withwater. The organic phase was dried (MgSO₄) and evaporated. Purificationby flash chromatography on silica gel (5×20 cm column) eluted with 1:24ether/dichloromethane gave title compound as a colorless oil, 1.06 g,41% yield.

E. α-(Diethoxyphosphinyl)-6-(hexyloxy)-2-naphthalenebutanesulfonic acid,cyclohexyl ester

To an argon-purged solution of 965 mg (1.66 mmol) of Part D compound and100 mg of 10% palladium-on-carbon in 15 mL of ethyl acetate in a 500 mLone-neck round bottom flask was attached a hydrogen-filled rubberbladder of approximately 1 L capacity. The reaction mixture wasvigorously stirred for 16 h, purged with nitrogen, filtered throughCelite and the filtrate evaporated. The oily residue was redissolved indichlormethane, filtered through a 0.75 μ (micron) filter andre-evaporated to give title compound as a colorless oil, 950 mg, 98%yield. The product was used without further purification.

F. 6-(Hexyloxy)-α-phosphono-2-naphthalenebutanesulfonic acid,dipotassium salt

To a stirred solution of 885 mg (1.52 mmol) of Part E compound in 10 mLof dichloromethane under argon at room temperature was added 800 μL ,(8.9 mmol) of bromotrimethylsilane. After 18 h, the resulting clearsolution was evaporated at 25° C. and the residue dissolved in 15 mL ofTHF. To this stirred solution was added 320 mg (1.9 mmol) of dried,finely ground potassium iodide and 3 mg (0.01 mmol) of 18-crown-6. Theresulting slurry was heated to reflux for 24 h, evaporated and thenstirred for 1 h with 9 mL (4.5 mmol) of 0.5M potassium hydroxidesolution. The solution was lyophilized and then purified by MPLC (2.5×20cm column of Mitsubishi Kasei Sepadbeads CHP-20P resin): 11.5 mLfractions, 7 mL/min flow rate, eluted with 200 mL of water and then agradient prepared from 400 mL of water and 450 mL of 1:1acetonitrile/water). Fractions 44-52 were collected and lyophilized togive title compound a white solid, 475 mg, 53% yield.

IR (KBr pellet) 3434, 3057, 2932, 2861, 1653, 605, 1181, 1076, 966 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ7.60 (d, 1H, J=9 Hz) 7.56 (s, 1H) 7.52 (d, 1H,J=8.3 Hz) 7.32 (d, 1H, J=8.3 Hz) 7.00 (s, 1H) 6.94 (d, 1H, J=9.0 Hz)3.78 (t, 2H, J=6.4 Hz) 2.83 (dm, 1H, J=18.0 Hz) 2.65 (m, 2H) 1.89 (m,4H) 1.48 (m, 2H) 1.16 (m, 2H) 1.07 (m, 4H) 0.67 (t, 2H, J=5.5 Hz) ppm.

Anal. Calc'd for C₂₀ H₂₇ K₂ O₇ PS.3.81 H₂ O: C, 40.76; H, 5.92; P, 5.26;S, 5.44 Found: C, 40.76; H, 5.81; P, 5.35; S, 5.35.

MS (FAB, + ions) m/e 559 (M+K), 521 (M+H).

EXAMPLE 10

4-[(5-Methyl-4-hexenyl)oxy]-α-phosphonobenzenebutanesulfonic acid,tripotassium salt

A. 5-Methyl-4-hexenoic acid, 1,1-dimethylethyl ester

To a stirred solution of 20.0 mL (142 mmol) of diisopropylamine in 160mL of THF under argon at -10° C. was added a solution of 56 mL (140mmol) of 2.5M n-butyllithium in hexane at a rate to keep the temperaturebelow 0° C. The resulting light yellow solution was stirred 15 min andto this reaction mixture was added 20 mL (115 mmol) of HMPA. After anadditional 10 min, the reaction was cooled to -75° C. and 18.8 mL (140mmol) of 1,1-dimethylethanol, acetate ester was added at a rate to keepthe temperature below -60° C. The resulting colorless solution wasstirred for 30 min and 20 g (134 mmol) of 4-bromo-2-methyl-2-butene wasadded over 10 min. The reaction was stirred at -75° C. for 6 h and thenwarmed to room temperature. After 16, h, the reaction Was quenched withsaturated ammonium chloride solution, extracted twice with ether, dried(MgSO₄) and evaporated. Purification by distillation (b.p. 64°-67° C. @6mmHg) gave title compound as a colorless oil, 20.1 g, 82% yield.

B. 5-Methyl-4-hexen-1-ol

To a stirred slurry of 1.71 g (45.1 mmol) of lithium aluminum hydride in50 mL of ether under nitrogen at 0° C. was added a solution of 15.5 g(84 mmol) of Part A compound in 20 mL of ether over 20 min. The reactionwas warmed to room temperature and stirred. After 24 h, the reaction wasquenched with 1M sodium potassium tartrate solution, extracted twicewith 50 mL portions of ether, dried (MgSO₄) and filtered. The extractwas distilled at atmospheric pressure through a 10 cm Vigreau columnuntil the head temperature reached 80° C. The residue was purified byvacuum distillation (b.p. 76°-77° C. @14 mmHg) to give title compound asa colorless oil, 9.06 g, 94% yield.

C. 4-[(5-Methyl-4-hexenyl)oxy]benzenepropanoic acid, ethyl ester

To a stirred solution of 1.14 g (10.0 mmol) of Part B compound, 1.94 g(10.0 mmol) of ethyl 4-hydroxyphenyl-3-propanoate and 2.62 g (10.0 mmol)of triphenylphosphine in 20 mL of THF at -10° C. under nitrogen wasadded a solution 2.0 mL (10 mmol) of diisopropyl diazodicarboxylate in20 mL of THF over the course of 2 hours. The resulting light yellowsolution was allowed to warm to room temperature, stirred 16 h and thenevaporated. The oily residue was triturated in 500 mL of hot hexaneuntil a precipitate formed. The solids were filtered off and treatedwith an additional 100 mL of hot hexane. The filtrates were combined andconcentrated. Purification of the residue by flash chromatography (5×15cm column, 1:1 dichloromethane/hexanes as elutent) gave 2.58 g, 89%yield, of title compound as a colorless oil.

D. 4-[(5-Methyl-4-hexenyl)oxy]benzenepropanol

To a stirred solution of 2.28 g (7.85 mmol) of Part C compound in 15 mLof THF at room temperature under nitrogen was added a 1M solution oflithium aluminum hydride (4.5 mL, 2.4 equivalents) in THF. After 20 min,the reaction was quenched with 1M sodium potassium tartrate solution andextracted twice with ether. The organic extracts were dried (MgSO₄) andevaporated twice from hexanes to give 1.88 g of title compound, 96%yield, as a colorless oil.

E. 1-(3-Iodopropyl)-4-[(5-methyl-4-hexenyl)oxy]benzene

To a stirred solution of 1.86 g (7.5 mmol) of Part D compound, 1.96 g(7.5 mmol) of triphenylphosphine and 1.13 g (16.5 mmol) of imidazole in25 mL of THF at room temperature under nitrogen was added 1.91 g (7.5mmol) of solid iodine, portionwise, over 30 min. After an additional 10min, the reaction mixture was diluted with hexanes and washed once withsaturated sodium bisulfite solution. The organic extracts were dried(MgSO₄) and evaporated. Purification by flash chromatography (5×12 cmcolumn, 1:4 dichloromethane/hexanes as elutent) gave 2.26 g, 84%, oftitle compound.

F. α-(Diethoxyphosphinyl)-4-[(5-methyl-4-hexenyl)oxy]benzenebutanesulfonic acid, cyclohexyl ester

To a stirred slurry of 120 mg (3.0 mmol, 60% mineral oil dispersion) ofsodium hydride in 3 mL of DMF under argon at -10° C. was added asolution of 1.12 g (3.56 mmol, 1.3 equiv.) Example 1A, Part B sulfonatein 1 mL of DMF. After addition was complete, the reaction was warmed toroom temperature and stirred for 30 min. To the resulting solution wasadded a solution of 1.00 g (2.79 mmol) of Part E compound in 1 mL ofDMF. The reaction was stirred for 16 h, diluted with ether and washedonce with 10% citric acid and thrice with water. The organic phase wasdried (MgSO₄) and evaporated. Purification by flash chromatography onsilica gel (5×20 cm column) eluted with 3:47 ether/dichloromethane gavetitle compound as a colorless oil, 685 mg, 45% yield.

G. 4-[(5-Methyl-4-hexenyl)oxy]-α-phosphonobenzenebutanesulfonic acid,tripotassium salt

A solution of 680 mg (1.25 mmol) of Part F compound in 10 mL of methanolunder argon at room temperature was saturated with ammonia gas. Theflask containing the reaction mixture was sealed and heated to 75° C.After 16 h, the reaction was cooled to room temperature and evaporatedunder dry conditions. The residue was dissolved in 10 mL ofdichloromethane and 1.7 mL (6.4 mmol) ofbis(trimethylsilyl)trifluoroacetamide and then 670 μL (5.0 mmol) ofbromotrimethylsilane was added. After 24 h, the resulting clear solutionwas evaporated at 25° C. and then stirred for 1 h with 8 mL (4 mmol) of0.5M potassium hydroxide solution. The solution was lyophilized and thenpurified by MPLC (2.5×20 cm column of Mitsubishi Kasei Sepadbeads HP-20resin): 11.5 mL fractions, 7 mL/min flow rate, eluted with 200 mL ofwater and then a gradient prepared from 400 mL of water and 450 mL of3:1 acetonitrile/water). Fractions 25-31 were collected and lyophilizedto give title salt as a white solid, 504 mg, 74% yield.

IR (KBr pellet) 3432, 2963, 2928, 2866, 1636, 512, 1242, 1202, 1080, 966cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ7.09 (d, 2H, J=8.5 Hz) 6.77 (d, 2H, J=8.5 Hz)5.06 (t, 1H, J=6.7 Hz) 3.85 (t, 1H, J=6.4 Hz) 2.79 (ddd, 1H, J=4.3, 6.0,18.0 Hz) 2.45 (m, 2H) 1.98 (m, 2H) 1.77 (m, 4H) 1.61 (m, 2H) 1.52 (s,3H) 1.43 (s, 3H) ppm.

Anal. Calc'd for C₁₇ H₂₄ K₃ O₇ PS.1.33 H₂ O: C, 37.49; H, 4.93; P, 5.69;S, 5.89 Found: C, 37.48; H, 5.28; P, 5.62; S, 5.64.

MS (FAB, + ions) m/e 559 (M+K), 521 (M+H), 483 (M-K+2H).

EXAMPLE 11

1-Phosphono-1-pentadecanesulfonic acid, tripotassium salt

A. (Diethoxyphosphinyl)methanesulfonic acid, 1-methylethyl ester

To a rapidly stirred solution of 8.28 g (60 mmol) of isopropylmethanesulfonate in 150 mL of THF at -73° C. (internal temp.) was added25 mL (60 mmol) of 2.4M n-butyllithium dropwise over 20 min. Theinternal temperature was not allowed to rise above -69° C. throughoutthe course of the addition. After an additional 15 min., 5.17 g (30mmol) of freshly distilled diethyl chlorophosphate was added at a rateto keep the solution temperature below -69° C. The reaction mixture wasstirred for 0.3 h at -73° C. and for 0.5 h at -40° C. when it wasquenched with 125 mL of saturated NH₄ Cl solution. The reaction mass waswarmed to room temperature and the THF removed under reduced pressure.The remainder was partitioned between methylene chloride and water (3×75mL). The extracts were dried (Na₂ SO₄), concentrated, and purified byflash chromatography (350 g silica gel) eluting with 1:1 methylenechloride/ether to provide 5.20 g (67%) of title compound as a colorlessoil.

TLC Silica gel (1:1 methylene chloride/ether) R_(f) =0.37.

¹ H NMR (CDCl₃, 270 MHz) δ5.05 (sept, 1H, J=6.0 Hz) 4.20 (quint, 4H,J=7.0 Hz) 3.75 (d, 2H, J=17.5 Hz) 1.50 (d, 6H, J=6.0 Hz) 1.40 (t, 6H,J=7.5 Hz) ppm.

B. 1-(Diethoxyphosphinyl)pentadecanesulfonic acid, 1-methylethyl ester

To a suspension of 0.10 g (4.38 mmol) of NaH in 7 mL of dry DMF at 0° C.under argon was added 1.20 g (4.38 mmol) of Part A compound over 5 min.to give a yellow solution. The reaction was allowed to warm to roomtemperature and stir for 0.5 h when 0.55 g (2.00 mmol) of tetradecanylbromide was added in one portion. The reaction mixture was stirred for24 h when it was quenched with 20 mL of saturated NaCl solution anddiluted with 50 mL of ether. The layers were separated, the organicsdried (Na₂ SO₄) and evaporated to provide a crude oil. Flashchromatography was performed on 100 g of silica gel eluting with 3:7ethyl acetate/hexane to provide 0.30 g (31%) of title compound in theform of a pale yellow oil.

TLC Silica gel (1:1 ethyl acetate/hexanes) R_(f) =0.50.

IR (film) 2924, 2853, 1466, 1358, 1260, 1177, 1053, 1024, 930 cm⁻¹.

¹ H NMR (CDCl₃, 300 MHz) 5.05 (sept., 1H, J=6.0 Hz) 4.20 (m, 4H) 3.35(dt, 1H, J=20.0, 6.4 Hz) 2.10 (m, 2H) 1.45 (m, 2H) 1.40 (d, 6H, J=6.5Hz) 1.30 (t, 6H, J=7.3 Hz) 1.20 (m, 22H) 0.85 (t, 3H, J=6.5 Hz) ppm.

Mass Spec (CI, + ions) m/e 488 (M+NH₄), 471 (M+H), 347 (M+H-SO₃ C₃ H₈).

C. 1-Phosphono-1-pentadecanesulfonic acid, tripotassium salt

To a stirred solution of 0.25 g (0.53 mmol) of Part B compound in 5 mLof dichloromethane at 0° C. and in the dark was added 4.24 g (2.12 mmol)of iodotrimethylsilane. The reaction was allowed to stir for 16 h whenthe solvent was evaporated and the semisolid residue pumped (∓1 mmpressure) for 0.5 h. The residue was dissolved by adding 3 mL of 1M (3.0mmol) KOH solution and freeze dried to provide an off white solid. Thesolid was purified by MPLC on a column of CHP20P gel (2.5 cm diam.×15 cmheight) eluting with water (100 mL) followed by a gradient created bythe gradual addition of 400 mL of acetonitrile to a reservoir of 250 mLof water. Approximately 7 mL fractions were collected. The acetonitrilewas removed under reduced pressure and the aqueous solution waslyophilized to provide 0.15 g (62%) of title salt as a white lyophilate.

TLC Silica gel (6:3:1 n-propanol/conc. ammonia/water) R_(f) =0.40.

IR (KBr) 3443, 2920, 2851, 1653, 1468, 1215, 1163, 1045, 966 cm⁻¹.

¹ H NMR (D₂ O, 300 MHz) δ2.80 (dt, 1H, J=19.0, 6.0 Hz) 1.85 (m, 2H) 1.50(m, 2H) 1.20 (m, 22H) 0.90 (t, 3H, J=6.0 Hz) ppm.

Mass Spec (FAB, + ions) m/e 525 (M+K), 487 (M+H).

Anal. Calc'd for C₁₅ H₃₀ O₆ K₃ PS+2.19 H₂ O: C, 34.24; H, 6.59; P, 5.89;S, 6.09 Found: C, 34.03; H, 6.88; P, 5.57; S, 6.02.

EXAMPLE 12

(E)-10,14-Dimethyl-1-phosphono-9,13-pentadecadiene-1-sulfonic acid,dipotassium salt

A. Dichloro[μ-[1-hexanolato(2-)-C⁶ :O¹ ]]dimagnesium

To a stirred solution of 11.00 g (80.0 mmol) of 6-chloro-1-propanol(Aldrich) in 20 mL of THF at -20° C. was added 27.0 mL (81.0 mmol) of3.0M methylmagnesium chloride in THF dropwise over 25 minutes. After 0.5hours at -20° C., the reaction was allowed to warm to room temperatureand 2.88 g (118.0 mmol) of magnesium turnings were added and thereaction was heated to reflux. The reaction was initiated by adding afew crystals of iodine at the start of reflux and after 1 hour ofheating. After 2 hours at reflux the reaction was cooled to roomtemperature providing the Grignard solution. The molarity of thereaction mixture was determined by titration: 5.20 mL (2.60 mmol) of a0.5M solution of 2-propanol in benzene was slowly added to a blood redsolution of 2-2'-biquinoline (indicator) in benzene and 2.0 mL of thefreshly prepared Grignard solution. The endpoint color was light greenand the molarity was determined to be 1.3M.

B. (E)-9,13-Dimethyl-8,12-tetradecadiene-1-ol

A solution of 21.5 mL (28.0 mmol) of 1.3M Part A Grignard reagent in THFand 5.0 mL of HMPA at 0° C. was treated dropwise with 1.21 g (7.0 mmol)of geranyl chloride in 7 mL of THF over 7 minutes. After the additionthe reaction was allowed to warm to room temperature and stir for 2hours, at which point the reaction was diluted with ether and quenchedwith 50 mL (50.0 mmol) of 1M HCl solution. The organic layer was washedtwo times with NH₄ Cl solution, dried over MgSO₄ and evaporated toprovide a crude oil. Flash chromatography was performed on 125 g ofsilica gel packed, loaded and eluted with 1:4 ethyl acetate/hexanes toprovide 1.10 (66%) of title alcohol as an amber oil.

TLC Silica gel (1:9 ethyl acetate:hexane) R_(f) =0.20.

IR (CCl₄ solution) 3636, 2928, 2854, 1450, 1377, 1055 cm⁻¹.

¹ H NMR (CDCl₃, 270 MHz): δ5.40 (q, 2H, J=7.0 Hz), 3.69 (t, 2H, J=7.0Hz), 2.25-1.85 (m, 8H), 1.75 (s, 3H), 1.70 (s, 6H), 1.65 (m, 2H), 1.39(s, 7H) ppm.

MS (CI, NH₃, + ions) 256 (M+NH₄).

C. (E) -9,13-Dimethyl-8,12-tetradecadien-1-yl iodide

To a stirred solution of 1.10 g (4.62 mmol) of Part B alcohol and 1.40mL (10.00 mmol) of triethylamine in 10 mL of methylene chloride at 0° C.was added 0.37 mL (4.80 mmol) of methanesulfonyl chloride dropwise over15 minutes. After 1 hour at 0° C. the reaction was diluted with etherand washed with aqueous solutions of NH₄ Cl, NaHCO₃, and brine. Theorganic layer was dried (MgSO₄) and concentrated under reduced pressureto provide 1.42 g (˜4.5 mmol) of the crude mesylate. The residual oilwas dissolved in 25 mL of acetone and treated with 3.00 g (20.0 mmol) ofNaI. The resulting suspension was heated to reflux for 4 hours anddiluted with ether, washed with brine, dried over MgSO₄, andconcentrated to provide a yellow oil. Flash chromatography was performedon 100 g of silica gel packed, loaded and eluted with hexanes to provide1.10 g (68% overall yield) of title iodide in the form of a colorlessoil.

TLC Silica gel (hexanes) R_(f) =0.45.

IR (CCl₄ solution) 2962, 2928, 2854, 1450, 1375, cm⁻¹.

¹ H NMR (CDCl₃, 270 MHz): δ5.41 (q, 2H, J=7.0 Hz), 3.47 (t, 2H, J=7.0Hz), 2.40-2.20 (m, 6H), 2.11 (quint., 2H, J=7.0 Hz), 1.97 (s, 3H), 1.89(s, 6H), 1.60 (m, 8H) ppm.

MS (CI, NH₃, + ions) 366 (M+NH₄), 348 (M).

D.(E)-α-(Diethyoxyphosphinyl)-10,14-dimethyl-9,13-pentadecadiene-1-sulfonicacid, cyclohexyl ester

To a stirred suspension of 191 mg (4.77 mmol, 2 eq.) of sodium hydride(as a 60% mineral oil dispersion) in 2 mL of dry dimethylformamide (DMF)at 0° C. was added a solution of 1.50 g (4.77 mmol, 2 eq.) of Example 1APart B sulfonate in 3 mL of DMF dropwise over 7 min. The solution waswarmed to RT and stirred for 50 min. To the resulting clear yellowsolution was added a solution of 831 mg (2.39 mmol, 1 eq.) of Part Ciodide in 3 mL of dry DMF dropwise over 5 min. The reaction was stirredat RT for 16 h diluted with ether (100 mL) and washed with water (50mL). The aqueous layer was extracted with ether (2×20 mL) and thecombined organic layers were washed with brine, dried (MgSO₄), andconcentrated to afford 1.77 g of a yellow oil. Flash chromatography wasperformed on 300 g of silica gel eluting with 30% ethyl acetate inhexanes. Fractions (40 mL each) containing clean product by TLC werepooled and concentrated to afford, after high vac (0.25 mmHg) removal ofsolvent remnants, 782 mg (61%) of title compound as a clear yellow oil.

TLC Silica gel (10% ether in CH₂ Cl₂): R_(f) 0.50.

E. (E)-10,14-Dimethyl-1-phosphono-9,13-pentadecadiene-1-sulfonic acid,dipotassium salt

To a solution of 515 mg (0.96 mol, 1 eq.) of Part D compound in 10 mL ofmethanol at 0° C. was bubbled ammonia until the solution was saturated.The reaction tube was then sealed and heated at 75° C. for 16 h. Thereaction mixture was allowed to cool to RT and then concentrated. Theoily residue was dried by coevaporation with toluene (2×). High vac(0.25 mmHg) removal of solvent remnants afforded 480 mg of light yellowoil.

To a solution of the yellow oil in 4 mL of dry dichloromethane at RT wasadded 636 μL (4.81 mmol, 5 eq.) of 2,4,6-collidine all at once. To theresulting clear light yellow solution was added 890 μL (6.74 mmol, 7eq.) of bromotrimethylsilane (TMSBr) dropwise over 3 min. As the TMSBrwas added a white precipitate formed and upon completion of TMSBraddition, 1 mL of dichloromethane was added to the thick reactionmixture to facilitate stirring. After 17 h at RT the reaction wasconcentrated and the resulting semisolid was placed on high vac (0.25 mmHg) for 1 h. The residue was dissolved by adding 4.8 mL (5 eq.) of 1Mpotassium hydroxide followed by 10 mL of water and lyophilized to affordan off-white lyophilate. The lyophilate was purified by MPLC on a columnof CHP20P (2.5 cm×25 cm) eluting initially with 150 mL of water followedby a gradient formed by the gradual addition of 400 mL of 30%acetonitrile in water to a reservoir containing 400 mL of 10%acetonitrile in water. Fractions containing clean product by HPLC(Method 8) were pooled and concentrated. The semisolid residue was takenup in water, filtered, concentrated and finally triturated with acetoneto afford, after high vac (0.025 mm Hg) removal of acetone remnants, 207mg (43%) of title salt in the form of a white solid.

TLC silica gel (5:4:1 n-propanol:ammonium hydroxide:water): R_(f) 0.39

IR (KBr) 3450(br), 2920, 2851, 1462, 1215, 1080, 1040 cm⁻¹.

¹ H NMR (D₂ O, 300 MHz) δ5.01 (t, 1H, J=7.6 Hz) 4.96 (t, 1H, J=7.0 Hz)2.87 (dt, 1H, J=18.1, 5.4 Hz) 1.90 (m, 2H) 1.82 (m, 6H) 1.49 (s, 3H)1.43 (m, 2H) 1.42 (s, 6H) 1.15 (bs, 8H) ppm.

¹³ C NMR (D₂ O, 75.6 MHz) δ135.7 132.7 125.5 124.7 61.0 (d, J_(CP) =126Hz) 39.4 29.6 29.4 29.2 (d, J_(CP) =7 Hz) 29.1 29.1 28.1 27.2 26.3 25.317.4 15.6 ppm.

MS (FAB, + ions) m/z 473 (M+H), 511 (M+K), 549 (M-H+K).

Anal. Calc'd for C₁₇ H₃₁ O₆ PSK₂.1.4 H₂ O: C, 41.01; H, 6.84; S, 6.44;P, 6.22 Found: 41.19; H, 6.52; S, 6.30; P. 5.95

EXAMPLE 13

(E,E)-6,10,14-Trimethyl-1-phosphono-5,9,13-pentadecatriene-1-sulfonicacid, phenyl ester, dipotassium salt

A. Methanesulfonic acid, phenyl ester

To a solution of 40.0 g (0.42 mol, 1 eq.) of phenol in 250 mL ofdichloromethane at 0° C. was added 250 mL (1.8 mol, 4.2 eq.) oftriethylamine. After 5 min, 49.3 mL (0.64 mol, 1.5 eq.) ofmethanesulfonyl chloride was added dropwise over 20 min. The resultingcloudy yellow solution was warmed to RT and stirred for 14 h. Thereaction was partitioned between ether (250 mL) and water (100 mL) andthe resulting organic layer was washed with cold 6N hydrochloric acid(2×200 mL). The combined aqueous layers were extracted with ether (2×50mL) and the combined organic layers were washed with water (100 mL),saturated sodium bicarbonate (200 mL), brine (200 mL), dried (MgSO₄) andconcentrated. Recrystallization of the orange solid from isopropanolafforded 44.94 g (61%) of the title compound as light yellow crystals;mp 58.0°-58.5° C.

TLC Silica gel (25% ethyl acetate in hexanes): R_(f) 0.29.

B. (Diethoxyphosphinyl)methanesulfonic acid, phenyl ester

To a turbid solution of 174 mL (0.174 mol, 1 eq.) of potassiumbis(trimethylsilyl)amide (20% by weight in tetrahydrofuran (THF) fromCallory Chem.) at -88° C. (internal temperature) was added a solution of30.0 g (0.174 mol, 1 eq.) of Part A compound in 75 mL of dry THF am arate to keep the internal temperature below -85° C. (addition took 20min). The reaction was stirred for 5 min at -85° C. then 15.2 mL (104mmol, 0.6 eq.) of freshly distilled diethylchlorophosphate was addeddropwise at a rate that kept the temperature below -72° C. (additiontook 13 min). After stirring at -65° C. for 1 h, the reaction wasquenched at -65° C. by the addition of a solution of 9.97 mL (0.174 mol,1 eq.) of acetic acid in 25 mL of THF over 5 min. The resulting solutionwas warmed to RT and the majority of the solvent was removed in vacuo.The residue was partitioned between dichloromethane (300 mL) and water(100 mL). The aqueous layer was extracted with dichloromethane (2×20 mL)and the combined organic layers were dried (MgSO₄) and concentrated toafford 43.82 g of solid/liquid mixture. The product was isolated byflash chromatography on silica gel (1000 g) eluting with 7:3 ethylacetate:hexanes. Fractions (40 mL each) containing clean product by TLCwere pooled to afford 17.19 g (54%) of title compound as a white solid;m.p. 50.5°-51.5° C.

TLC Silica gel (10% ether in dichloromethane): R_(f) 0.38.

C.(E,E)-1-(Diethyoxyphosphinyl)-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, phenyl ester

To a suspension of 333 mg (8.32 mmol, 2 eq.) of sodium hydride (60%mineral oil dispersion) in 5 mL of dry dimethylformamide (DMF) at 0° C.was added a solution of 2.56 g (8.32 mmol, 2 eq.) of Part B compound in5 mL of dry DMF. The hetero-geneous bubbling solution was warmed to RTand stirred for 30 min. To the resulting homogeneous yellow solution wasadded a solution of 1.50 g (4.16 mmol, 1 eq.) of Example 1 Part C iodidein 5 mL of dry DMF and the reaction was stirred for 41 h at RT. Thereaction was diluted with ether (150 mL) and washed with water (50 mL).The aqueous layer was extracted with ether (2×15 mL) and the combinedorganic layers were washed with brine, dried (MgSO₄) and concentrated toafford 3.11 g of a yellow oil. The product was isolated via flashchromatography on silica gel (200 g) eluting with 35% ethyl acetate inhexanes. Fractions (40 mL each) containing clean product by TLC werepooled and concentrated to afford 1.39 g (62%) of title compound as aclear light yellow oil.

TLC Silica gel (10% ether in hexanes): R_(f) 0.66.

D. (E,E)-6,10,14-Trimethyl-1-phosphono-5,9,13-pentadecatriene-1-sulfonicacid, phenyl ester, dipotassium salt

To a solution of 500 mg (0.92 mmol, 1 eq.) of Part C compound in 4 mL ofdichloromethane at RT was added 367 μL (2.8 mmol, 3 eq.) of2,4,6-collidine followed by 488 μL (3.7 mmol, 4 eq.) ofbromotrimethylsilane (TMSBr). After 28 h an additional 100 μL (0.76mmol, 0.8 eq.) of TMSBr was added to consume intermediate monoester.After 18 h (46 h total), reaction mixture was concentrated and placed onhigh vac (0.25 mmHg) for 2 h. The resulting yellow oil was dissolved byadding 1.9 mL (1.9 mmol, 2.1 eq.) of 1M potassium hydroxide. Theresulting cloudy solution (pH 8.42) was lyophilized and the light brownlyophilate was chromatographed on a column of CHP20 (2.5 cm×25 cm)eluting initially with 150 mL of water then with a gradient formed bythe gradual addition of 400 mL of acetonitrile to a reservoir containing400 mL of water. Fractions containing clean product by HPLC were pooledand concentrated. The residue was taken up in a minimal amount of water,filtered and lyophilized to afford 411 mg of title salt in the form ofan off-white lyophilate.

TLC Silica gel (7:2:1 n-propanol:ammonium hydroxide:water): R_(f) 0.38.

IR (KBr): 3410 (br), 2965, 2924, 1636, 1487, 1339, 1194, 1148, 1098cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ7.10 (m, 4H) 6.99 (t, 1H, J=7..1 Hz) 4.97 (t,1H, J=6.4 Hz) 4.74 (m, 2H) 3.42 (dt, 1H, J=17.1, 5.6 Hz) 2.08 (m, 2H)1.98 (m, 1H) 1.88 (m, 1H) 1.68-1.47 (m, 10H) 1.37 (s, 3H) 1.29 (s, 3H)1.20 (s, 3H) 1.17 (s, 3H) ppm.

¹³ C NMR (D₂ O, 75.6 MHz) δ148.8 135.7 134.4 130.4 130.0 127.0 124.4124.3 124.3 122.4 62.3 (d, J_(CP) =107 Hz) 39.8 39.6 29.0 (d, J_(CP) =5Hz) 28.1 27.5 26.8 26.7 25.3 17.3 15.9 15.7 ppm.

MS (FAB, + ions): m/z 523 (M-K+2H)⁺, 561 (M+H)⁺, 599 (M+K)⁺.

Anal. Calc'd for C₂₄ H₃₅ O₆ PSK₂.0.84 H₂ O: C, 50.05: H, 6.42; P, 5.38;S, 5.72 Found: C. 50.05; H, 6.74; P, 5.11; S, 5.45

EXAMPLE 14

(E,E)-9,13,17-Trimethyl-1-phosphono-8,12,16-octadecatriene-1-sulfonicacid triponassium salt

A. Dichloro[μ-[1-propanolato(2-)-C^(3:) O¹ ]]dimagnesium

A modification of the procedure of G. Cahiez et al was employed(Tetrahedron Letters, 1978, 3013-4): To a stirred solution of 1.89 g (20mmol) of 3-chloropropanol in 20 mL of THF under argon at -20° C. wasadded 10 mL (20 mmol) of 2M phenylmagnesium chloride in THF over 15minutes. After 10 minutes at 20° C., the reaction was allowed to warm toRT, 730 mg (30 mmol) of magnesium turnings were added and the reactionwas heated to reflux. Two 40 μL portions of 1,2-dibromoethane wereadded, the first portion injected at the start of reflux, and the secondafter 1 hour. After refluxing for a total of 2 hours, the reaction wasallowed to cool to RT and was diluted with 37 mL of THF for atheoretical concentration of 0.3M.

B. (E.E)-8,12,16-Trimethyl-7,11,15-heptadecatrien-1-ol

Copper (I) iodide (18 mg, 0.097 mmol) was added to a solution of Example1 Part C iodide (3.50 g, 9.72 mmol) in THF (50 mL) under argon, and themixture was cooled to 0° C. The Part A Grignard solution (23.4 mL, 0.5Min THF, 11.7 mmol) was added dropwise over 10 min, and the resultantcloudy white reaction was stirred at 0° C. for 10 min. The ice bath wasremoved and the reaction was stirred at RT for 1 h. Isopropanol (1.5 mL)was added dropwise slowly to quench the reaction. followed by additionof 1M KHSO₄ (30 mL). The mixture was stirred for 5 min at RT, whereupontwo layers separated. Diethyl ether (250 mL) was added, and the organiclayer was washed with water (20 mL), saturated NH₄ Cl (50 mL), and brine(50 mL), then dried over MgSO₄. Evaporation gave a yellow oil which waspurified by flash chromatography on 100 g silica gel eluting with 15:85EtOAc/hexanes to give title compound (2.62 g, 92%) as a colorless oil.

C. (E,E)-17-Iodo-2,6,10-trimethyl-2,6,10-heptadecatriene

A solution of iodine (861 mg, 3.39 mmol) in THF (4 mL) was addeddropwise to a solution of Part B compound (900 mg, 3.08 mmol),triphenylphosphine (888 mg, 3.39 mmol), and imidazole (461 mg, 6.78mmol) in THF (10 mL) under argon at RT. The reaction became slightlyexothermic during addition. The resultant brown reaction mixture wasstirred at RT for 5 min, diluted with hexane (70 mL) and washed with 10%aqueous sodium bisulfite and brine (10 mL each), then dried over MgSO₄.Silica gel (4 g) was added to the filtrate, and the solvent wasevaporated to give a white solid. Purification by flash chromatographyon 50 g silica gel eluting with hexane gave title compound (1.19 g, 96%)as a colorless oil.

D.(E,E)-1-(Diethoxyphosphinyl)-9,13,17-trimethyl-8,12,16-octadecatriene-1-sulfonicacid, cyclohexyl ester

A solution of Example 1A, Part B sulfonate (958 mg, 3.05 mmol) in DMF (2mL) was added dropwise over 5 min to a suspension of dry sodium hydride(67 mg, 2.79 mmol) in DMF at -15° C. under argon (note: H₂ evolution).The cooling bath was removed and the suspension was stirred at RT for 1h, whereupon a clear yellow solution was obtained. A solution of Part Ccompound (1.02 g, 2.54 mmol) in DMF (3 mL) was added dropwise over 3min, and the reaction was stirred at RT for 23 h. The reaction wasquenched by addition of saturated NH₄ Cl (2 mL), and the resultantmixture was partitioned between diethyl ether (100 mL) and water (20mL). The organic layer was washed with water (10 mL) and brine (50 mL),then dried over MgSO₄. Evaporation gave an opaque oil which was purifiedby flash chromatography on 125 g silica gel eluting with 20:80EtOAc/hexane followed by 30:70 EtOAc/hexane to give title compound (981mg, 66%) as a colorless oil.

E. (E,E)-9,13,17-Trimethyl-1-phosphono-8,12,16-octadecatriene-1-sulfonicacid, tripotassium salt

Ammonia was bubbled through a solution of Part D compound (876 mg, 1.49mmol) in methanol (20 mL) at 0° C. for 15 min. The reaction mixture wasthen heated at 75 C. in a sealed tube for 20 h, cooled to RT, andconcentrated in vacuo to give a yellow gum. The crude product wasdissolved in CH₂ Cl₂ (7 mL) under argon.Bis(trimethylsilyl)trifluoroacetamide (2.0 mL, 7.45 mmol) was added andthe reaction was stirred at RT for 10 min. Bromotrimethylsilane (786 mL,5.96 mmol) was added dropwise and the resultant cloudy yellow reactionmixture was stirred at RT for 22 h. Additional bromotrimethylsilane (197mL, 1.49 mmol) was added to the clear yellow solution and the reactionwas stirred for another 18 h at RT. The reaction was concentrated invacuo then pumped at high vacuum for 1 h to give a yellow oil, which wasdissolved in 1N KOH (7.5 mL, 7.5 mmol) and stirred at RT for 2 h. Theresultant heterogeneous yellow mixture was lyophilized to give a tansolid, which was purified by chromatography on CHP20P gel (2.5×20 cmcolumn) eluting with water followed by a gradient created by the gradualaddition of acetonitrile to a reservoir of water. The product fractionswere concentrated to approximately a 10 mL volume, then lyophilized. Thewhite solid was dissolved in water (600 mL) and acetone (2 mL) wasadded. The white semi-solid which precipitated was washed with acetone(3×2 mL) then pumped at high vacuum to give title salt (517 mg, 62%) asa white solid.

TLC Silica gel (6:3:1 n-propanol/NH₄ OH/H₂ O): R_(f) =0.21

IR (KBr) 2924, 2855, 1624, 1449, 1383, 1213, 1148, 1092, 1044, 966, 714cm⁻¹.

¹ H NMR (D₂ O, 300 MHz) δ5.04 (m, 3H) 2.76 (ddd, 1H, J=18.3, 5.9, 4.9Hz) 1.84 (m, 12H) 1.50 (s, 3H) 1.44 (s, 3H) 1.42 (s, 6H) 1.40 (m, 2H)1.17 (br s, 6H) ppm.

¹³ C NMR (D₂ O, 75 MHz) δ135.15 131.56 125.27 124.53 124.44 61.69(d,J=123 Hz) 39.54 39.46 29.85 29.72 29.60 29.26 28.71 27.86 26.49 25.2917.32 15.66 ppm.

MS (FAB, + ions) m/z 527 (M+2H-K), 565 (M+H), 603 (M+K).

Anal. Calc'd for C₂₁ H₃₆ K₃ O₆ PS. 1.0 equiv H₂ O: C, 43.27; H, 6.57; P,5.31; S, 5.50. Found: C, 42.93; H, 6.93; P, 5.03; S, 5.87.

EXAMPLE 15

(E,E)-1-(Ethoxyhydroxyphosphinyl)-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, dipotassium salt

To a solution of 0.44 g (0.80 mmol) of Example 1A Part C compound and 10mL of methanol in a sealable tube at 0° C. was added NH₃ (g) until thesolution was saturated. The tube was sealed and placed in an oil bath at70° C. for 24 h, at which point the tube was opened and the volatilesremoved under reduced pressure. The remainder was dissolved in dryethanol and evaporated two times (2×10 mL) leaving an amber oil. The oilwas dissolved in 4.0 mL of a 1:1 ethanol/water solution and treated with0.45 g (8.00 mmol) of potassium hydroxide. The mixture was heated to 80°C. for 72 h when the solvent was evaporated and the residue pumped (≈0.5mm pressure) for 0.5 h. The remainder was purified by MPLC on a columnof CHP20P gel (2.5 cm diam.×20 cm height) eluting with water (150 mL)followed by a gradient created by the gradual addition of 400 mL ofacetonitrile to a reservoir of 350 mL of water. Approximately 7 mLfractions were collected. Pure fractions were combined and theacetonitrile was removed under reduced pressure. The aqueous solutionwas lyophilized to provide 0.30 g (74%) of title salt as a whitelyophilate.

TLC Silica gel (6:3:1 n-propanol/conc. ammonia/water) R_(f) =0.55.

IR (KBr) 3459, 3052, 2969, 2926, 2859, 1636, 1445, 1383, 1221, 1105,1190, 1055, 1038, 945 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ5.19 (t, 1H, J=7.0 Hz) 5.11 (q, 2H, J=6.5 Hz)3.90 (m, 2H) 3.00 (dt, 1H, J=18.4, 6.0 Hz) 2.10-1.80 (m, 12H), 1.61 (s,3H) 1.56 (s, 3H) 1.54 (s, 6H) 1.55 (m, 2H) 1.17 (t, 3H, J=7.2 Hz) ppm.

Mass Spec (FAB, + ions) m/e 551 (M+K), 513 (M+H).

Anal. Calc'd for C₂₀ H₃₅ O₆ K₂ PS: C, 46.85; H, 6.88; P, 6.04; S, 6.25Found: C, 46.76; H, 6.89; P, 5.67; S, 6.60.

EXAMPLE 16

(E)-8,12-Dimethyl-1-phosphono-7,11-tridecadiene-1-sulfonic acid,dipotassium salt

A. (E)-7,11-Dimethyl-6,10-dodecadienoic acid, 1,1-dimethylethyl ester

To a stirred solution of 1.10 mL (7.71 mmol) of freshly distilleddiisopropylamine in 7.0 mL of THF under argon at -78° C. was added 3.20mL (5.14 mmol) of 1.6M n-butyllithium in hexanes to give a pale yellowsolution. The solution was allowed to warm to 0° C. for 15 minutes thencooled again to 78° C., at which time 693 μL (5.14 mmol) oft-butyl-acetate (t-BuOAc) was added neat. After an additional 15 minutesat -78° C., 1.79 mL (10.28 mmol) of HMPA was added followed by theaddition of 1.50 g (5.14 mmol) of Example 2, Part F iodide in 5 mL ofTHF dropwise over 5 minutes. The reaction was stirred at -78° C. for 2hours at which time it was warmed to room temperature, diluted with 50mL of ether and quenched with saturated NH₄ Cl. The organic layer waswashed with water, brine, dried, (MgSO₄) and evaporated to provide 1.39g of a pale yellow oil. Flash chromatography was performed on 100 g ofsilica gel eluting with hexane (1 L) and 9:1 hexane/EtOAc (1 L). Productfractions were combined and evaporated to provide 1.15 g (92%) of titlecompound as a pale yellow oil.

TLC Silica gel (9:1 hexane/ethyl acetate) R_(f) =0.70.

IR (CCl₄) 2976, 2928, 2857, 1732, 1454, 1368, 1155 cm⁻¹.

¹ H NMR (270 MHz, CDCl₃): δ5.20 (t, 1H, J=6.9 Hz), 5.18 (t, 1H, J=6.9Hz), 2.30 (t, 2H, J=7.3 Hz), 2.14 (m, 2H), 2.08 (m, 4H), 1.77 (s, 3H),1.69 (m+s, 8H), 1.53 (s, 9H), 1.47 (m, 2H) ppm.

MS (CI-NH₃, + ions) m/e 298 (M+NH₄), 281 (M+H).

B. (E)-7,11-Dimethyl-6,10-dodecadien-1-ol

To a stirred solution of 234 mg (6.16 mmol) of lithium aluminum hydridein 10 mL of ether at 0° C. under argon was added dropwise over 10minutes 1.15 g (4.10 mmol) of Part A ester. The reaction was stirred for1 hour at which time it was quenched by the following: 234 μL of water,234 μL of 15% NaOH in water and 700 μL of water. The granular mixturewas stirred and dried (Na₂ SO₄) for 0.5 hours at which time the mixturewas filtered through a celite cake and the cake was washed with etherfollowed by dichloromethane. The filtrate was evaporated to provide 834mg of a colorless oil. Flash chromatography was performed on 100 g ofsilica gel eluting with 1:1 hexane/EtOAc (1 L). Pure product fractionswere combined and evaporated to provide 824 mg (96%) of title alcohol asa colorless oil.

TLC Silica gel (9:1 hexane/ethyl acetate) R_(f) =0.15.

IR (CCl₄) 3300, 2928, 2856, 1450, 1377, 1151, 1107, 1055 cm⁻¹.

¹ H NMR (270 MHz, CDCl₃): δ5.13 (t, 1H, J=7.0 Hz), 5.10 (t, 1H, J=7.0Hz), 3.63 (t, 2H, J=6.5 Hz), 2.10 (m, 2H), 2.01 (m, 4H), 1.68 (s, 3H),1.60 (s, 6H), 1.56 (m, 2H), 1.36 (m, 4H) ppm.

MS (CI--NH₃) m/e 228 (M+NH₄).

C. (E)-12-Iodo-2,6-dimethyl-2,6-dodecadiene

To a stirred solution of 820 mg (3.90 mmol) of Part B alcohol in 8 mL ofTHF under argon at room temperature was added 3.07 g (11.71 mmol) oftriphenylphosphine, 797 mg (11.71 mmol) of imidazole and 1.98 g (7.81mmol) of iodine. After 1 hour, the brown solution was diluted with etherand washed with saturated sodium sulfite, brine, dried (MgSO₄) andevaporated. Flash chromatography was performed on 100 g of silica geleluting with hexane. Pure product fractions were combined and evaporatedto provide 913 mg (73%) of title iodide as a colorless oil.

TLC Silica gel (Hexane) R_(f) =0.46.

IR (CCl₄) 2922, 2853, 1449, 1383 cm⁻¹.

¹ H NMR (270 MHz, CDCl₃): δ5.22 (t, 1H, J=6.5 Hz), 5.19 (t, 1H, J=6.5Hz), 3.29 (t, 2H, J=7.0 Hz), 2.14 (m, 2H), 2.09 (m, 4H), 1.93 (quint,2H, J=7.0 Hz), 1.78 (s, 3H), 1.70 (s, 6H), 1.45 (m, 4H)ppm.

MS (CI--NH₃, + ions) m/e 338 (M+NH₄), 320 (M).

D. (E)-1-(Diethoxyphosphinyl)-8,12-dimethyl-7,11-tridecadiene-1-sulfonicacid, cyclohexyl ester

To a stirred suspension of 187 mg (4.68 mmol, 1.5 eq.) of sodium hydride(as a 60% mineral oil dispersion) in 1.5 mL of dry dimethylformamide(DMF) at 0° C. was added a solution of 1.47 g (4.68 mmol, 1.5 eq.) ofExample 1A Part B compound in 2 mL of DMF dropwise over 5 min. Thesolution was warmed to RT and stirred for 30 min. To the resulting clearyellow solution was added a solution of 1.00 g (3.12 mmol, 1 eq.) ofPart C iodide in 3 mL of dry DMF dropwise over 5 min. The reaction wasstirred at RT for 70 h, diluted with ether (100 mL) and washed withwater (50 mL). The aqueous layer was extracted with ether (2×15 mL) andthe combined organic layers were washed with brine, dried (MgSO₄), andconcentrated to afford 1.14 g of a yellow oil. Flash chromatography wasperformed on 250 g of silica gel eluting with 30% ethyl acetate inhexanes. Fractions (40 mL each) containing clean product by TLC werepooled and concentrated to afford, after high vac (0.25 mmHg) removal ofsolvent remnants, 410 mg (26%) of title compound as a clear yellow oil.

TLC Silica gel (10% ether in CH₂ Cl₂): R_(f) 0.49.

E. (E)-8,12-Dimethyl-1-phosphono-7,11-tridecadiene-1-sulfonic acid,dipotassium salt

To a solution of 400 mg (0.79 mol, 1 eq.) of Part D compound in 8 mL ofmethanol in a sealable tube at 0° C. was bubbled ammonia until thesolution was saturated. The reaction tube was then sealed and heated at75° C. for 17 h. The reaction mixture was allowed to cool to RT and thenconcentrated. The oily residue was dried by coevaporation with toluene(2×). High vac (0.25 mmHg) removal of solvent remnants a light yellowoil.

To a solution of the yellow oil in 5 mL of dry dichloromethane at RT wasadded 522 μL (3.95 mmol, 5 eq.) of 2,4,6-collidine. To the resultingclear light yellow solution was added 729 μL (5.53 mmol, 7 eq.) ofbromotrimethylsilane (TMSBr) dropwise over 4 min. As the TMSBr was addeda white precipitate formed and the reaction became exothermic. An icebath was used to cool reaction mixture until addition of TMSBr wascomplete. After 16 h at RT the reaction was concentrated and theresulting semisolid was placed on high vac (0.25 mm Hg) for 2 h. Theresidue was dissolved by adding 4.95 mL (6.3 eq.) of 1M potassiumhydroxide followed by 5 mL of water and lyophilized to afford anoff-white lyophilate. The lyophilate was purified by MPLC on a column ofCHP20P (2.5 cm×25 cm) eluting initially with 150 mL of water followed bya gradient formed by the gradual addition of 400 mL of 50% acetonitrilein water to a reservoir containing 400 mL of 10% acetonitrile, in water.Fractions containing clean product by HPLC were pooled and concentrated.The semisolid residue was taken up in water, filtered, concentrated andfinally triturated with acetone to afford, after high vac (0.025 mm Hg)removal of acetone remnants, 305 mg (77%) of title salt as a whitesolid.

TLC silica gel (5:4:1 n-propanol:ammonium hydroxide:water): R_(f) 0.39

IR (KBr): 3450(br), 2924, 2855, 1653, 1447, 1209, 1148, 1044 cm⁻¹.

¹ H NMR (D₂ O, 300 MHz) δ5.10 (t, 1H, J=6.9 Hz) 5.03 (t, 1H, J=6.5 Hz)2.73 (ddd, 1H, J=17.9, 6.5, 4.6 Hz) 1.95 (m, 2H) 1.86 (m, 4H) 1.75 (m,2H) 1.52 (s, 3H) 1.46 (s, 6H) 1.41 (m, 2H) 1.18 (m, 4H) ppm.

¹³ C NMR (D₂ O, 75.6 MHz) δ136.4 133.7 125.6 124.7 61.8 (d, J_(CP) =121Hz) 39.0 29.5 (d, J_(CP) =7 Hz) 29.2 29.0 28.7 27.5 26.0 25.0 17.2 15.5ppm.

MS (FAB, + ions): m/z 445 (M+H), 483 (M+K), 521 (M-H+2K).

Anal. Calc'd for C₁₅ H₂₇ O₆ PSK₂.3.2 H₂ O: C, 35.87; H, 6.70; S, 6.38;P, 6.17 Found: C, 35.91; H, 6.30; S, 6.11; P, 6.10

EXAMPLE 17

α-Phosphono[1,1'-biphenyl]-4-heptanesulfonic acid, tripotassium salt

A. 4-(6-Iodohexyl) [1.1'-biphenyl]

A(1). 6-([1,1'-Biphenyl]-4-yl)-6-hexyl-1-ol

To suspension of 0.361 g (2.04 mmol, 0.02 eq) of palladium chloride and1.07 g (4.08 mmol, 0.04 eq) of triphenylphosphine in 300 mL ofdiethylamine at room temperature was added 26.1 g (112 mmol, 1.1 eq) of4-bromobiphenyl (from Aldrich) followed by 0.766 g (4.08 mmol, 0.04 eq)of copper (I) iodide (99.999% pure, from Aldrich). After 5 min, 10.0 g(102 mmol, 1.0 eq) of 5-hexyn-1-ol (from Aldrich) was added neat. After43 h, the reaction was concentrated and the residue was partitionedbetween water (250 mL) and CH₂ Cl₂ (250 mL). The aqueous solution wasextracted with CH₂ Cl₂ and the combined organic solutions wereconcentrated. To remove the catalyst the residue was filtered throughsilica gel (40 g) eluting initially with CH₂ Cl₂ then with CH₂ Cl₂containing 2% EtOAc. Concentration afforded 31.9 g of a brownish orangesolid which was chromatographed on silica gel (400 g) eluting with 2%EtOAc in CH₂ Cl₂ (4 L), then 4% EtOAc in CH₂ Cl₂ (2 L). The isolatedsolid was then recrystallized from chloroform/hexanes to afford 16.2 g(64%) of the title compound as a white solid; m.p. 64.0°-64.5° C.

TLC Silica gel (25% EtOAc in hexanes): R_(f) 0.14.

A(2). [1.1'-Biphenyl]-4-hexanol

To a solution of 9.0 g (36 mmol, 1 eq) of Part A(1) alcohol in 100 mL ofTHF was added 300 mg (0.36 mmol, 0.01 eq) of 10% palladium on activatedcarbon. The resulting heterogeneous mixture was placed under an H₂atmosphere at RT. After 67 h, the reaction was filtered through Celiteand the filter cake was washed with Et₂ O and CH₂ Cl₂. Concentrationafforded 9.07 g (99%) of the title compound as a fluffy white solid;m.p. 77.0°-77.5° C.

TLC Silica gel (25% EtOAc in hexanes): R_(f) 0.19.

A(3). 4-(6-Iodohexyl) [1.1'-biphenyl]

To a solution of 7.00 g (28 mmol, 1.0 eq) of Part A(2) biphenylhexanolin 30 mL of dry THF were added 8.66 g (33 mmol, 1.2 eq) oftriphenylphosphine and 4.50 g (66 mmol, 2.4 eq) of imidazole. To theresulting homogeneous solution was added dropwise a solution of 8.38 g(33 mmol, 2.4 eq) of iodine in 40 mL of dry THF over 25 min. After 45min, the reaction was diluted with Et₂ O and washed with 10% aqueoussodium bisulfite, brine and dried (MgSO₄). The solution was filtered andthe volume was reduced approximately by 50%. Silica gel (35 g) was addedand the remainder of the solvent was removed. The product adsorbed ontosilica gel was loaded onto a pre-equilibrated column (hexanes) of silicagel (20 g) and eluted with hexanes. Fractions containing clean productwere pooled and concentrated to afford 9.40 g (94%) of the titlecompound as a clear, colorless oil.

TLC Silica gel (25% EtOAc in hexanes): R_(f) 0.69.

B. α-(Diethoxyphosphinyl) [1,1'-biphenyl]-4-heptanesulfonic acid, phenylester

To a stirred suspension of 329 mg (8.23 mmol, 2 eq.) of sodium hydride(as a 60% mineral oil dispersion) in 3 mL of dry dimethylformamide (DMF)at 0° C. was added a solution of 2.54 g (8.23 mmol, 2 eq.) of Example 13Part B compound in 6 mL of DMF dropwise over 10 min. The solution waswarmed to RT and stirred for 30 min. To the resulting clear yellowsolution was added a solution of 1.50 g (4.12 mmol, 1 eq.) of Part Aiodide in 6 mL of dry DMF dropwise over 5 min. The reaction was stirredat RT for 43 h, diluted with ether (200 mL) and washed with water (100mL). The aqueous layer was extracted with ether (2×25 mL) and thecombined organic layers were washed with brine, dried (MgSO₄), andconcentrated to afford 3.36 g of a yellow oil. Flash chromatography wasperformed on 400 g of silica gel eluting with 40% ethyl acetate inhexanes. Fractions (40 mL each) containing clean product by TLC werepooled and concentrated to afford, after high vac (0.25 mmHg) removal ofsolvent remnants, 1.06 g of a clear yellow oil, as well as 742 mg of thedesired product contaminated with dialkylated material. The contaminatedmaterial was rechromatographed on 200 g of silica gel and the cleanproduct was combined with the previously isolated product to afford1.375 g (61%) of title compound as a clear light yellow oil.

TLC Silica gel (10% ether in CH₂ Cl₂): R_(f) 0.57.

C. α-Phosphono[1,1'-biphenyl]-4-heptanesulfonic acid, tripotassium salt

To a solution of 600 mg (1.1 mmol, 1 eq.) of Part B compound in 5 mL ofdioxane at RT was added 1.1 mL (1.1 mmol, 1 eq.) of 1M potassiumhydroxide. The initially turbid solution became homogeneous within 2 h.After 19 h, starting material was still evident by TLC as well as alower Rf spot (presumably due to over hydrolysis). An additional 1.1 mL(1.1 mmol, 1 eq.) of KOH was added and reaction was stirred for 16 h (35h total) at RT. The reaction mixture was concentrated and the residualyellow oil was co-evaporated with toluene (4∴) to remove water andplaced on high vac (0.25 mmHg) for 2 h to afford a yellow solid.

To a heterogeneous solution of the yellow solid in 5 mL of drydichloromethane at RT was added 1.45 mL (11.0 mmol, 10 eq.) ofbromotrimethylsilane (TMSBr) dropwise over 3 min. As the TMSBr was addedthe solution began to clear and upon completion of TMSBr addition thereaction was nearly homogeneous. After 17 h, an additional 750 μL (5.7mmol, 5.1 eq.) of TMSBr was added to complete consumption of theintermediate monoester. After 22 h (39 h total ) at RT, the reaction wasconcentrated and the resulting oil was placed on high vac (0.25 mm Hg)for 13 h. The residue was dissolved by adding 4.4 mL (4.4 mmol, 4 eq.)of 1M potassium hydroxide followed by 20 mL of water and sonicating at40° C. for 10 min. The crude product was purified by MPLC on a column ofCHP20P (2.5 cm ×25 cm) eluting initially with 150 mL of water followedby a gradient formed by the gradual addition of 400 mL of acetonitrilein water to a reservoir containing 400 mL of water. Fractions containingclean product were pooled and concentrated. The semisolid residue wastaken up in water, filtered and lyophilized to afford 243 mg (39%) of awhite lyophilate.

TLC silica gel (5:4:1 n-propanol: ammonium hydroxide:water): R_(f) 0.38.

IR (KBr): 3403(br), 2928, 2857, 1651, 1202, 1163, 1072 cm⁻¹.

¹ H NMR (D₂ O, 300 MHz): δ7.52 (d, 2 H, J=7.8 Hz) 7.45 (d, 2H, J=8.0 Hz)7.35 (t, 2H, J=7.5 Hz) 7.24 (t, 1H, J=8.0 Hz) 7.22 (d, 2H, J=8.0 Hz)2.73 (ddd, 1H, J=17.8, 6.6, 4.4 Hz) 2.51 (t, 2H, J=7.5 Hz) 1.74 (m, 2H)1.48 (m, 2H) 1.39 (m, 2H) 1.20 (bs, 4H) ppm.

¹³ C NMR (D₂ O, 75.6 MHz): δ143.4 140.6 137.9 129.4 129.3 127.6 127.0126.9 61.8 (d, J_(CP) =121 Hz) 34.7 30.9 29.5 (d, J_(CP) =6 Hz) 29.128.7 28.5 ppm.

MS (FAB): m/z 489 (M-K+2H)⁺, 527 (M+H)⁺.

Anal. Calcd for C₁₉ H₂₂ O₆ PSK₃.2.31 H₂ O: C, 40.15; H, 4.72; S, 5.64;P, 5.45 Found: C, 40.15; H, 4.89; S, 5.60; P, 5.47

EXAMPLE 18

(E)-4-(4'-Pentyl[1,1'-biphenyl]-4-yl)-1-phosphono-3-butene-1-sulfonicacid, tripotassium salt

A. α-Ethenyl-4'-pentyl[1,1'-biphenyl]-4-methanol, acetate ester

To a stirred solution of 3.03 g (10.0 mmol) of4-bromo-4'-pentyl[1,1'-biphenyl] in 20 mL of THF under argon at -78° C.was added a solution of 12.5 mL (21.2 mmol) of 1.7M t-butyllithium inpentane over 1 h. A dark-colored slurry had formed. This was warmed to0° C. and the resulting organic solution was stirred for 25 min. To thisreaction mixture was added 0.8 mL (12 mmol, 1.2 equivalents) of freshlydistilled acrolein an a rate to keep the temperature below 5° C. Afteran additional 30 min, the reaction was quenched with saturated ammoniumchloride solution, extracted twice with ether, dried (MgSO₄) andevaporated. The resulting yellow solid was dissolved in 50 mL ofdichloromethane and stirred under argon. To this solution was added 2.5mL (18 mmol) of triethylamine, 1.5 mL (15 mmol) of acetic anhydride and20 mg (0.16 mmol) of 4-N,N-dimethylaminopyridine at room temperature.After 14 h, the reaction mixture was evaporated, redissolved in ether,washed once with 10% citric acid, once with water and once withsaturated sodium bicarbonate solution. The extract was dried (MgSO₄) andevaporated. Purification by flash chromatography on silica gel (5×25 cmcolumn, 2:3 dichloromethane/hexanes as elutent) gave title compound as acolorless oil, 2.20 g, 68% yield.

B.(E)-1-(Diethoxyphosphinyl)-4-(4'-pentyl[1,1'-biphenyl-4-yl)-3-butene-1-sulfonicacid, 1-methylethyl ester

To a stirred solution of 1.50 g (4.65 mmol) of Part B compound, 2.7 mL(10.7 mmol, 2.3 equiv.) of bis(trimethylsilyl)acetamide, 2.5 g (9.3mmol, 2.0 equiv.) of Example 11, Part A sulfonate and 125 mg (0.5 mmol)of triphenylphosphine in 10 mL of THF under argon was added 270 mg (0.24mmol) of tetrakis(triphenylphosphine)palladium. The resulting mixturewas heated to 45° C. for 2 hour. The reaction was cooled, evaporated,diluted with ether and washed once with 10% citric acid and thrice withwater. The organic phase was dried (MgSO₄) and evaporated. Purificationby flash chromatography on silica gel (5×20 cm column) eluted with 4:96ether/dichlo-romethane gave title compound as a colorless oil, 1.65 g,66% yield.

C. (E)-4-(4'-Pentyl[1,1'-biphenyl]-4-yl)-1-phosohono-1-butene-1-sulfonicacid.

A solution of 670 mg (1.24 mmol) of Part B compound in 10 mL of methanolunder argon at room temperature was saturated with ammonia gas. Theflask containing the reaction mixture was sealed and heated to 75° C.After 16 h, the reaction was cooled to room temperature and evaporatedunder dry conditions. The residue was dissolved in 10 mL ofdichloromethane and 560 μL (6.4 mmol) ofbis(trimethylsilyl)trifluoroacetamide and then 670 μL (5.0 mmol) ofbromotrimethylsilane was added. After 24 h, the resulting clear solutionwas evaporated at 25° C. and then stirred for 1 h with 8 mL (4 mmol) of0.5M potassium hydroxide solution. The solution was lyophilized and thenpurified by MPLC (2.5×20 cm column of Mitsubishi Kasei Sepadbeads HP-20resin): 11.5 mL fractions, 7 mL/min flow rate, eluted with 200 mL ofwater and then a gradient prepared from 400 mL of water and 450 mL of3:1 acetonitrile/water). Fractions 42-50 were collected and lyophilizedto give title salt as a white solid, 505 mg, 85% yield.

IR (KBr pellet) 3430, 2928, 2855, 1636, 1497, 1202, 1078, 968 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ7.28 (m, 4H) 7.21 (d, 2H, J=7.1 Hz) 6.88 (d,2H, J=7.3 Hz) 6.40 (m, 2H) 2.94 (dm, 1H, J=17.1 Hz) 2.82 (m, 1H) 2.67(m, 1H) 2.25 (t, 2H, J=5.5 Hz) 1.27 (dq, 2H, J=6.0 Hz) 0.98 (m, 4H) 0.58(t, 3H, J=6.8 Hz,) ppm.

Anal. Calc'd for C₂₁ H₂₄ K₃ o₆ PS.2.2 H₂ O: C, 42.58; H, 4.83; P, 5.23;S, 5.41 Found: C, 42.18; H, 5.19; P, 5.63; S, 5.42.

MS (FAB, + ions) m/e 591 (M+K), 553 (M+H), 515 (M-K+2H).

EXAMPLE 19

α-Phosphono-4'-Pentyl[1,1]-biphenyl]-4-butanesulfonic acid, tripotassiumsalt

A. α-(Diethoxyphosphinyl)-4'-propyl[1,1'-biphenyl]-4-butanesulfonicacid, 1-methylethyl ester

To an argon-purged solution of 550 mg (1.02 mmol) of Example 18 Part Bcompound and 100 mg of 10% palladium-on-carbon in 25 mL of ethyl acetatein a 200 mL one-neck round bottom flask was attached a hydrogen-filledrubber bladder of approximately 1 L capacity. The reaction mixture wasvigorously stirred for 16 h, purged with nitrogen, filtered throughCelite and the filtrate evaporated. The oily residue was triturated inhexanes and re-evaporated to give title compound as a colorless oil, 545mg, 99% yield. The product was used without further purification.

B. α-Phosphono-4'-pentyl[1,1'-biphenyl]-4-butanesulfonic acid,tripotassium salt

To a stirred solution of 520 mg (1.00 mmol) of Part A compound in 5 mLof dichloromethane under argon at room temperature was added 400 μL (4.5mmol) of bromotrimethylsilane. After 18 h, the resulting clear solutionwas evaporated at 25° C. and the residue dissolved in 10 mL of THF. Tothis stirred solution was added 330 mg (2 mmol) of dried, finely groundpotassium iodide and 3 mg (0.01 mmol) of 18-crown-6. The resultingslurry was heated to reflux for 24 h, evaporated and then stirred for 1h with 6 mL (4.5 mmol) of 0.5M potassium hydroxide solution. Thesolution was lyophilized and then purified by MPLC (2.5×20 cm column ofMitsubishi Kasei Sepadbeads CHP-20P resin): 11.5 mL fractions, 7 mL/minflow rate, eluted with 200 mL of water and then a gradient prepared from400 mL of water and 450 mL of acetonitrile). Fractions 26-31 werecollected and lyophilized to give title salt as a white solid, 400 mg,69% yield.

IR (KBr pellet) 3424, 3088, 2928, 2859, 1663, 1499, 1202, 1082, 1049,966 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) 7.34 (d, 1H, J=7.7 Hz) 7.31 (d, 1H, J=7.8 Hz)7.18 (d, 1H, J=7.8 Hz) 7.02 (d, 1H, J=7.7 Hz) 2.80 (dt, 1H, J=17.8, 5.1Hz) 2.35 (t, 1H, J=7.0 Hz) 1.81 (m, 4H) 1.36 (m, 2H) 1.06 (m, 4H) 0.63(t, 2H, J=6.8 Hz) ppm.

Anal. Calc'd for C₂₁ H₂₆ K₃ O₆ PS.1.42 H₂ O: C, 43.46; H, 5.01; P, 5.34;S, 5.52 Found: C, 43.46; H, 4.93; P, 5.37; S, 5.25.

MS (FAB, + ions) m/e 593 (M+K), 555 (M+H), 517 (M-K+2H).

EXAMPLE 20

4-(2-Naphthalenyl)-α-phosphonobenzenebutanesulfonic acid, tripotassiumsalt

A. 2-(4-Bromophenyl)naphthalene

To a stirred solution of 4.14 g (20.0 mmol) of 2-bromonaphthalene in 50mL of THF at -78° C. under nitrogen was added a solution of 23.5 mL(40.0 mmol, 1.7M in pentane) of t-butyllithium over 10 minutes. Theresulting slurry was stirred for 30 minutes and then warmed to 0° C. for15 minutes. To this deep indigo solution was added a solution of 3.50 g(25.6 mmol) of thrice-fused zinc chloride in 25 mL of THF. The resultinglight yellow solution was warmed to room temperature and stirred for 1hour. After cooling to -78° C., a solution of 5.66 g (20.0 mmol)1-bromo-4-iodobenzene and 300 mg (0.26 mmol) oftetrakis(triphenylphosphine)palladium in 20 mL of THF was added over thecourse of 15 minutes. After an additional 20 min, the cooling bath wasremoved, the reaction stirred at room temperature for 16 hours and thenquenched with 50 mL of 2M hydrochloric acid. The mixture was extractedthrice with ether, the extracts combined, washed once with saturatedsodium bicarbonate solution and once with 10% sodium thiosulfate. Theorganic extract was dried (MgSO₄) and evaporated. The crude product waspurified by flash chromatography on silica gel (5×25 cm column, hexanesas elutent) to give 4.05 g (72%) of title compound as a white solid, mp121°-123° C.

B. α-Ethenyl-4-(2-naphthalenyl)benzenemethanol, acetate ester

To a stirred solution of 2.59 g (9.13 mmol) of Part A compound in 20 mLof THF at -78° C. under nitrogen was added a solution of 10.8 mL (18.4mmol, 1.7M in pentane) of t-butyllithium over 20 minutes. The resultingmagenta slurry was warmed to 0° C. and stirred for 1 h. To the resultingsolution was added 0.8 mL (14 mmol) of freshly distilled acrolein over 5min. The resulting light yellow solution was stirred for 1 hour and thenquenched with saturated ammonium chloride. The mixture was extractedtwice with ether, dried (MgSO₄) and evaporated to give a white solid.

The solid was dissolved in 50 mL of dichloromethane, stirred undernitrogen at room temperature and treated with 2.0 mL (14.4 mmol) oftriethylamine, 1.23 mL (13 mmol) of acetic anhydride and 50 mg (0.4mmol) of DMAP. After 16 h, the reaction mixture was evaporated,redissolved in ether and washed once with 10% citric acid solution, oncewith brine and once with saturated sodium bicarbonate solution. Theorganic phase was dried (MgSO₄) and evaporated. The crude product waspurified by flash chromatography on silica gel (5×20 cm column, 1:1dichloromethane/hexanes as elutent) to give 1.83 g (66% from Part Acompound) of title compound as a white solid, mp 61°-63° C.

C. (E)-1-(Diethoxyphosphinyl)-4-[4-(2-napthalenyl)phenyl]-3-butene-1-sulfonic acid, 1-methylethyl ester

To a stirred solution of 1.55 g (5.13 mmol) of Part B compound, 2.75 mL(12.9 mmol, 2.5 equivalents) of bis(trimethylsilyl)acetamide, 2.81 g(10.2 mmol, 2.0 equivalents) of Example 11, Part A sulfonate and 125 mg(0.48 mmol) of triphenylphosphine in 10 mL of THF under nitrogen wasadded 270 mg (0.24 mmol) of tetrakis(triphenylphosphine)-palladium. Theresulting mixture was heated to 45° C. for 2 h. The reaction was cooledand evaporated and pumped at room temperature @0.2 Torr for 24 hours.The residue was diluted with dichloromethane and evaporated onto 5 g ofsilica gel. Purification by flash chromatography on silica gel (5×20 cmcolumn) eluted with 1:16 ether/dichloromethane gave title compound as ayellow oil, 950 mg, 36% yield.

D. α-(Diethoxyphosphinyl)-4-(2-naphthalenyl)benzenebutanesulfonic acid,1-methylethyl ester

To a nitrogen-purged solution of 950 mg (1.85 mmol) of Part C compoundand 350 mg of 10% Pd/C in 25 mL of ethyl acetate in a 200 mL one-neckround bottom flask was attached a hydrogen-filled rubber bladder ofapproximately 1 L capacity. The reaction mixture was vigorously stirredfor 16 h, purged with nitrogen, filtered through Celite and the filtrateevaporated. The oily residue was redissolved in dichlormethane, filteredthrough a 0.75 m filter and re-evaporated to give title compound as acolorless oil, 960 mg, 100% yield. The product was used without furtherpurification.

E. 4-(2-Naphthalenyl)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt

To a stirred solution of 950 mg (1.81 mmol) of Part D compound in 10 mLof dichloromethane under nitrogen at room temperature was added 1.4 mL(10.5 mmol) of bromotrimethylsilane. After 24 h, the resulting clearsolution was evaporated at 25° C. and the residue dissolved in 10 mL ofTHF. To this stirred solution was added 0.5 g (3 mmol) of dried, finelyground potassium iodide and 6 mg (0.02 mmol) of 18-crown-6. Theresulting slurry was heated to reflux for 20 h, evaporated and thenstirred for 1 h with 12 mL (6 mmol) of 0.5M potassium hydroxidesolution. The solution was lyophilized and then purified by MPLC (2.5×20cm column of CHP20P resin): 11.5 mL fractions, 7 mL/min flow rate,eluted with 200 mL of water and then a gradient prepared from 400 mL ofwater and 450 mL of 2:1 acetonitrile/water). Fractions 66-72 werecollected and lyophilized to give title salt as a white solid, 560 mg,55% yield.

IR (KBr pellet) 3418, 3055, 2934, 2864, 1661, 1503, 1339, 1196, 1078,966 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ7.68 (s, 1H) 7.57 (m, 3H) 7.37 (dd, 1H, J=1.3,8.6 Hz) 7.31 (d, 1H, J=8.1 Hz) 7.27 (m, 2H) 7.14 (d, 1H, J=8.1 Hz) 2.82(ddd, 1H, J=2.1, 6.4, 17.5 Hz) 2.56 (m, 2H) 1.74 (m, 4H) ppm.

MS (FAB, + ions) m/e 573 (M+K), 535 (M+H), 497 (M-K+2H).

Anal. Calc'd for C₂₀ H₁₈ K₃ PSO₆.3H₂ O: C, 43.04; H, 3.72; P, 5.55; S,5.74 Found: C, 43.04; H, 3.86; P, 5.79; S, 6.09.

EXAMPLE 21

4-Phenoxy-α-phosphonobenzenebutanesulfonic acid, tripotassium salt

A. α-Ethenyl-4-phenoxybenzenemethanol

tert-Butyllithium (24.5 mL, 1.7M in pentane, 42.2 mmol) was addeddropwise over 30 min to a solution of 4-bromodiphenyl ether (5.00 g,20.1 mmol) in THF (50 mL) at -78° C. under argon. The cooling bath wasremoved and the bright yellow reaction mixture was warmed to 0° C. over20 min. The reaction was stirred at 0° C. for 30 min, at which time atan-colored solution developed. Freshly distilled acrolein (1.6 mL, 24mmol) was added dropwise over 5 min. The colorless reaction mixture wasstirred at 0° C. for 15 min, then quenched by addition of saturated NH₄Cl (10 mL). The mixture was diluted with diethyl ether (200 mL) and theorganic layer was washed with water (20 mL) and brine (50 mL), thendried over MgSO₄. Evaporation gave a crude oil which was purified byflash chromatography on silica gel (400 g) eluted with a step gradientof 10:90 EtOAc/hexane to 15:85 EtOAc/hexane to 20:80 EtOAc/hexane toprovide title compound (3.31 g, 73%) as a colorless oil.

B. α-Ethenyl-4-phenoxybenzenemethanol, acetate ester

Acetic anhydride (1.7 mL, 18 mmol) and 4-dimethylaminopyridine (18 mg,0.15 mmol) were added to a solution of Part A alcohol (3.30 g, 14.6mmol) and triethylamine (4.1 mL, 29.2 mmol) in CH₂ Cl₂ (50 mL), and thereaction was stirred at RT under argon for 1.5 h. The reaction mixturewas diluted with CH₂ Cl₂ (50 mL) and washed with water (10 mL) and brine(20 mL), then dried over MgSO₄. Evaporation gave a yellow oil which waspurified by flash chromatography on silica gel (100 g) eluted with 10:90EtOAc/hexane to give title compound (3.83 g, 98%) as a pale yellow oil.

C. (E)-1-(Diethoxyphosphinyl)-4-(4-phenoxyphenyl)-3-butene-1-sulfonicacid, 1-methylethyl ester

Tetrakis(triphenylphosphine)palladium (200 mg, 0.17 mmol) was added to amixture of Part B compound (1.50 g, 5.60 mmol), Example 11, Part Acompound (3.07 g, 11.2 mmol), bis(trimethylsilyl)acetamide (2.76 mL,11.2 mmol), and triphenylphosphine (73 mg, 0.28 mmol) in THF (20 mL).The, reaction was heated at reflux for 45 min, cooled to RT, andconcentrated in vacuo to give a gold-colored oil. The crude product waspurified by flash chromatography on silica gel (150 g) eluted with agradient of 40:60 EtOAc/hexane to 50:50 EtOAc/hexane to afford titlecompound (914 mg, 34%) as a colorless oil.

D. α-(Diethoxyphosphinyl)-4-phenoxybenzenebutanesulfonic acid,1-methylethyl ester

A mixture of Part C compound (900 mg, 1.87 mmol) and 10% palladium oncarbon (50 mg) in EtOAc (6 mL) was stirred at RT under an atmosphere ofH₂ (balloon) overnight (18 h), then was filtered through a pad of Celitewith the aid of EtOAc. Evaporation gave title compound (855 mg, 94%) asa colorless oil.

E. 4-Phenoxy-α-phosphonobenzenebutanesulfonic acid, tripotassium salt

Ammonia gas was bubbled through a solution of Part D compound (780 mg,1.61 mmol) in methanol (15 mL) for 15 min at RT. During the saturation,the solution turned yellow and became slightly exothermic. The reactionmixture was heated at 75° C. in a sealed tube overnight (17 h), then wascooled to RT. The reaction was concentrated in vacuo, and the residuewas azeotroped with toluene (2×10 mL) to give a thick yellow syrup.

The crude product was dissolved in CH₂ Cl₂ (5 mL) under argon andbromotrimethylsilane (1.5 mL, 11.3 mmol) was added dropwise. The cloudyyellow reaction was stirred at RT overnight, concentrated in vacuo, andpumped at high vacuum for 3 h.

The crude residue was dissolved in 1N KOH (8.1 mL, 8.1 mmol) and stirredat RT for 30 min. The reaction was heterogeneous. Additional 1N KOH (1.6mL, 1.6 mmol) was added along with water (5 mL). The still heterogeneousreaction mixture was lyophilized to give a beige solid, which waspurified by chromatography on CHP20P gel (2.5×20 cm column) eluted withwater followed by a gradient created by the gradual addition ofacetonitrile to a reservoir of water. The product fractions wereconcentrated to approximately a 5 mL volume, then lyophilized to providetitle salt (488 mg, 61%) as a white solid.

TLC (silica gel) (6:3:1 n-propanol/NH₄ OH/H₂ O): R_(f) =0.15

IR (KBr) 3042, 2936, 2864, 1663, 1589, 1507, 1489, 1240, 1198, 1076, 966cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ7.27 (t, 2H, J=7.9 Hz) 7.19 (d, 2H, J=8.3 Hz)7.04 (t, 1H, J=7.5 Hz) 6.91 (d, 2H, J=7.7 Hz) 6.87 (d, 2H, J=8.3 Hz)2.79 (dm, 1H) 2.52 (m, 2H) 2.00-1.63 (m, 4H) ppm.

¹³ C NMR (D₂ O, 75 MHz) δ157.22 154.56 138.96 130.15 130.08 123.66119.04 118.57 61.69 (d, J=120 Hz) 34.74 31.53 (d, J=7Hz) 28.61 (d, J=2Hz) ppm.

MS (FAB, + ions) m/z 463 (M+2H-K), 501 (M+H), 539 (M+K).

Anal. Calc'd for C₁₆ H₁₆ K₃ O₇ PS. 1.0 equiv H₂ O: C, 37.05; H, 3.50; P,5.97; S, 6.18. Found: C, 36.77; H, 3.86; P, 6.42; S, 6.48.

EXAMPLE 22

1-Phosphono-7-(4-propylphenoxy)-1-heptanesulfonic acid, tripotassiumsalt

A. 1-[(6-Bromohexyl)oxy]-4-propylbenzene

A solution of diisopropylazodicarboxylate (2.12 g, 10.5 mmol) in THF (25mL) was added via syringe pump over 1.5 h to a mixture of 4-propylphenol(purchased from Aldrich Chemical Co.) (1.36 g, 10.0 mmol),6-bromo-1-hexanol (purchased from Aldrich Chemical Co.) (1.81 g, 10.0mmol), and triphenylphosphine (2.75 g, 10.5 mmol) in THF (25 mL) at 0°C. under argon. The slightly yellow reaction was stirred at 0° C. for 30min, whereupon additional triphenylphosphine (262 mg, 1.00 mmol) wasadded, followed by addition of diisopropyl-, azodicarboxylate (200 mL,1.0 mmol) over 30 min. The reaction was allowed to warm to RT, at whichtime silica gel (15 g) was added. The mixture was concentrated in vacuoand the white powder obtained was purified by flash chromatography onsilica gel (150 g) eluted with a step gradient of hexane to 2:98EtOAc/hexane. The slightly impure product obtained was rechromatographedon silica gel (150 g) eluted with 1:99 EtOAc/hexane to give titlecompound (2.00 g, 67%) as a colorless oil.

B. 1-[(6-Iodohexyl)oxy]-4-propylbenzene

A mixture o f Part A compound (1.85 g, 6.19 mmol), sodium iodide (4.65g, 31.0 mmol), and anhydrous sodium bicarbonate (520 mg, 6.19 mmol) inmethyl ethyl ketone (15 mL) was brought to reflux and maintained at thattemperature for 2 h, then allowed to cool to RT. The solvent was removedfrom the colorless reaction in vacuo and the residue was partitionedbetween diethyl ether (70 mL) and water (20 mL). The organic layer waswashed with water (10 mL) and brine (10 mL), then dried over MgSO₄.Evaporation gave title compound (2.09 g, 98%) as a opaque oil.

C. 1-(Diethoxyphosphinyl)-7-(4-propylphenoxy)-1-heptanesulfonic acid,cyclohexyl ester

A solution of Example 1A, Part B sulfonate (4.65 g, 14.8 mmol) in DMF (5mL ) was added dropwise over 5 min to a suspension of dry sodium hydride(283 mg, 11.8 mmol) in DMF (5 mL) at -15° C. under argon (note: H₂evolution). The cooling bath was removed and the suspension was stirredat RT for 30 min, whereupon a clear yellow solution was obtained. Asolution of Part B iodide (2.04 g, 5.90 mmol) in DMF (10 mL) was addeddropwise over 5 min, and the reaction was stirred at RT overnight. Thereaction was quenched by addition of saturated NH₄ Cl (10 mL), and theresultant mixture was partitioned between diethyl ether (50 mL) andwater (50 mL). The aqueous layer was extracted with diethyl ether (50mL). The organic extracts were combined and washed with water (20 mL)and brine (2×20×20 mL), then dried over MgSO₄. Evaporation gave a yellowoil which was purified by flash chromatography on silica gel (200 g)eluted with 30:70 EtOAc/hexane to give title compound (2.12 g, 68%) as acolorless oil.

D. 1-Phosphono-7-(4-propylphenoxy)-1-heptanesulfonic acid, tripotassiumsalt

Ammonia gas was bubbled through a solution of Part C compound (810 mg,1.52 mmol) in methanol (15 mL) for 10 min at RT. During the saturation,the solution turned yellow and became slightly exothermic. The reactionmixture was heated at 75° C. in a sealed tube overnight (20 h), thencooled to RT. The reaction was concentrated in vacuo, and the residuewas azeotroped with toluene (2×10 mL) to give a white semi-solid.

The crude product prepared above was dissolved in CH₂ Cl₂ (8 mL) underargon and bromotrimethylsilane (1.4 mL, 10.6 mmol) was added dropwise.The cloudy yellow reaction was stirred at RT overnight (19 h),concentrated in vacuo, and pumped at high vacuum for 3 h.

The crude residue prepared above was dissolved in 1N KOH (7.6 mL, 7.6mmol) and stirred at RT for 15 min, diluted with water (5 mL), thenlyophilized to give a white solid. Purification was performed bychromatography on CHP20P gel (2.5×20 cm column) eluted with waterfollowed by a gradient created by the gradual addition of acetonitrileto a reservoir of water. The product fractions were concentrated toapproximately a 5 mL volume, then lyophilized to provide title salt (406mg, 53%) as a white solid.

TLC (silica gel) (6:3:1 n-propanol/NH₄ OH/H₂ O): R_(f) =0.21

IR (KBr) 2932, 2868, 1636, 1512, 1200, 1074, 966 cm⁻¹.

¹ H NMR (D₂ O, 300 MHz) δ7.05 (d, 2H, J=8.4 Hz) 6.79 (d, 2H, J=8.4 Hz)3.90 (t, 2H, J=6.6 Hz) 2.72 (ddd, 1H, J=4.5, 6.3, 17.8 Hz) 2.37 (t, 2H,J=7.5 Hz) 1.93-1.10 (m, 12H) 0.71 (t, 3H, J=7.3 Hz) ppm.

¹³ C NMR (D₂ O, 75 MHz) δ156.24 136.23 129.78 115.03 69.14 61.76 (d,J=120 Hz) 36.41 29.42 (d, J=7Hz) 28.92 28.63 28.54 25.24 24.31 13.07ppm.

MS (FAB, + ions) m/z 509 (M+H), 547 (M+K).

Anal. Calc'd for C₁₆ H₂₄ K₃ O₇ PS. 1.6 equiv H₂ O: C, 35.75; H, 5.10; P,5.76; S, 5.97. Found: C, 35.79; H, 5.49; P, 5.54; S, 5.95.

EXAMPLE 23

α-Phosphono-4-(4-propylphenoxy)benzenebutanesulfonic acid, tripotassiumsalt

A. 4-(4-Propylphenoxy)benzaldehyde

Anhydrous potassium carbonate (14.9 g, 0.12 mol) was added to a mixtureof 4-propylphenol (13.6 g, 0.10 mol) and 4-fluorobenzaldehyde (12.4 g,0.10 mol) in N,N-dimethylacetamide (100 mL) under argon. Theheterogeneous mixture was brought to reflux, maintained at thattemperature for 5 h, then cooled to RT. Water (100 mL) and CH₂ Cl₂ (100mL) were added, resulting in a tri-phase system. The bottom layer wasremoved; the middle layer was dried over MgSO₄ ; and, the top layer wasextracted with CH₂ Cl₂ (100 mL) and dried over MgSO₄. The dried layerswere combined and concentrated in vacuo at 50° C. to give an orange oil.The crude product was purified by distillation to give title compound(16.6 g, 69%) as a colorless oil. bp 138°-150° C. (0.2 mm Hg)

B. α-Ethenyl-4-(4-propylphenoxy)benzenemethanol acetate ester

A solution of Part A compound (2.00 g, 8.33 mmol) in THF (15 mL) wasadded dropwise over 10 min to a solution of vinylmagnesium bromide (9.2mL, 1.0M in THF, 9.2 mmol) in THF (15 mL) at -40° C. under argon. Thereaction was warmed to -20° C. over 30 min, whereupon the heterogeneousmixture went to clear yellow. Additional vinylmagnesium bromide (1.5 mL,1.0M in THF, 1.5 mmol) was added dropwise. The reaction was stirred at-20° C. for 10 min, then quenched by addition of saturated NH₄ Cl (10mL). The solvent was removed in vacuo, and the mixture was diluted withdiethyl ether (50 mL). The organic layer was washed with water (10 mL),1N HCl (10 mL), and brine (20 mL), then dried over MgSO₄. Evaporationgave the alcohol (2.6 g) as a yellow oil.

Acetic anhydride (0.94 mL, 10.0 mmol), triethylamine (2.3 mL, 16.7mmol), and 4-dimethylaminopyridine (10 mg, 0.08 mmol) were added to asolution of the crude alcohol in CH₂ Cl₂ (30 mL) under argon. The yellowreaction was stirred at RT for 2.5 h, diluted with CH₂ Cl₂ (50 mL), andwashed with water and brine (20 mL each), then dried over MgSO₄.Evaporation gave a heterogeneous yellow oil, which was purified by flashchromatography on silica gel (150 g) eluted with 3:97 EtOAc/hexane togive title compound (1.85 g, 72%) as a pale yellow oil.

C.(E)-1-(Diethoxyphosphinyl)-4-[4-(4-propylphenoxy)phenyl]-3-butene-1-sulfonicacid, 1-methylethyl ester

Tetrakis(triphenylphosphine)palladium (196 mg, 0.17 mmol) was added to amixture of Part B compound (1.74 g, 5.61 mmol), Example 11, Part Acompound (3.07 g, 11.2 mmol), bis(trimethylsilyl)acetamide (2.8 mL, 11mmol), and triphenylphosphine (73 mg, 0.28 mmol) in THF (20 mL). Thereaction was heated at 45° C. for 3 h, cooled to RT, and concentrated invacuo to give a yellow oil. The crude product was purified by flashchromatography on silica gel (200 g) eluted with a step gradient of30:70 EtOAc/hexane to 40:60 EtOAc/hexane to afford title compound (706mg, 24%) as a colorless oil.

D. 1-(Diethoxyphosphinyl)-4-(4-propylphenoxy) benzenebutanesulfonicacid, 1-methylethyl ester

A mixture of Part C compound (700 mg, 1.34 mmol) and 10% palladium oncarbon (40 mg) in EtOAc (5 mL) was stirred at RT under an atmosphere ofH₂ (balloon) overnight, then was filtered through a pad of Celite withthe aid of CH₂ Cl₂. Evaporation gave title compound (669 mg, 95%) as acolorless oil.

E. α-Phosphono-4-(4-propylphenoxy)benzenebutanesulfonic acid,tripotassium salt

Ammonia gas was bubbled through a solution of Part D compound (610 mg,1.16 mmol) in methanol (10 mL) for 10 min at RT. During the saturation,the solution turned yellow and became slightly exothermic. The reactionmixture was heated at 75° C. in a sealed tube overnight (20 h), thencooled to RT. The reaction was concentrated in vacuo, and the residuewas azeotroped with toluene (2×10 mL) to give a pale yellow oil.

The crude product prepared above was dissolved in CH₂ Cl₂ (6 mL) underargon and bromotrimethylsilane (1.1 mL, 8.1 mmol) was added dropwise.The cloudy yellow reaction was stirred at RT overnight (19 h),concentrated in vacuo, and pumped at high vacuum for 3 h.

The crude residue prepared above was dissolved in 1N KOH (5.8 mL, 5.8mmol) and stirred at RT for 15 min, diluted with water (5 mL), thenlyophilized to give a white solid. Purification was performed bychromatography on CHP20P gel (2.5×20 cm column) eluted with waterfollowed by a gradient created by the gradual addition of acetonitrileto a reservoir of water. The product fractions were concentrated toapproximately a 5 mL volume, then lyophilized to provide title salt (445mg, 71%) as a white solid.

TLC (silica gel) (6:3:1 n-propanol/NH₄ OH/H₂ O): R_(f) =0.18

IR (KBr) 2959, 2870, 1503, 1240, 1200, 1078, 966 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ7.16 (d, 2H, J=8.6 Hz) 7.10 (d, 2H, J=8.6 Hz)6.83 (2d, 4H, J=6.4, 6.8 Hz) 2.79 (ddd, 1H, J=4.3, 6.2,. 16.9 Hz), 2.50(m, 2H) 2.42 (t, 2H, J=7.5 Hz) 1.97-1.62 (m, 4H) 1.45 (sextet, 2H, J=7.5Hz) 0.73 (t, 3H, J=7.5 Hz) ppm.

¹³ C NMR (D₂ O, 75 MHz) δ154.93 138.64 130.01 118.70 118.63 61.54 (d,J=120 Hz) 36.56 34.73 31.51 (d, J=7 Hz) 28.52 24.27 13.06 ppm.

MS (FAB, + ions) m/z 543 (M+H), 581 (M+K).

Anal. Calc'd for C₁₉ H₂₂ K₃ O₇ PS. 2.0 equiv H₂ O: C, 39.43; H, 4.53; P,5.35: S, 5.54. Found: C, 39.63; H, 4.70; P, 5.18; S, 5.50.

EXAMPLE 24

(E,E)-1-(Diethoxyphosphinyl)-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, sodium salt

To a solution of 0.50 g (0.91 mmol) of Example 1A Part C compound and 10mL of methanol in a sealable tube at 0° C. was added NH₃ (g) until thesolution was saturated. The tube was sealed and, placed in an oil bathat 70° C. for 24 h, at which point the tube was opened and the volatilesremoved under reduced pressure. The remainder was dissolved with 1.20 mL(1.20 mmol) of 1N sodium hydroxide solution. The compound was purifiedby MPLC by loading the basic solution on a column of CHP20P gel (2.5 cmdiam.×20 cm height) and eluting with water (150 mL) followed by agradient created by the gradual addition of 400 mL of acetonitrile to areservoir of 350 mL of water. Approximately 7 mL fractions werecollected. Pure fractions (#30-34) were combined and the acetonitrilewas removed under reduced pressure. The aqueous solution was lyophilizedto provide 0.39 g (87%) of title salt as an amber oil.

TLC Silica gel (6:3:1 n-propanol/conc. ammonia/water) R_(f) =0.80.

IR (CHCl₃) 3459, 2969, 2926, 2859, 1647, 1445, 1236, 1165, 1098, 1069,1034, 970 cm⁻¹.

¹ H NMR (CD₃ OD, 300 MHz) δ5.15 (m, 3H) 4.18 (quint., 4H, J=7.0 Hz) 3.22(dt, 1H, J=18.4, 6.0 Hz) 2.10-1.80 (m, 12H) 1.70 (s, 3H) 1.65 (s, 3H)1.60 (s, 6H) 1.60 (m, 2H) 1.30 (t, 3H, J=7.0 Hz) ppm.

Mass Spec (FAB, + ions) m/e 509 (M+Na).

Anal. Calc'd for C₂₂ H₄₀ O₆ NaPS-0.73 H₂ O: C, 53.91; H, 8.31; P, 6.32;S, 6.54 Found: C, 53.91; H, 8.23; P, 6.17; S, 6.33.

EXAMPLE 25

(E)-6-Methyl-10-phenyl-1-phosphono-5-decene-1-sulfonic acid,tripotassium salt

A. 5-Methyl-9-phenyl-non-4-en-1-ol

To a solution of 1.5 g (4.26 mmol) of the Example 35, Part B iodide in10 mL of THF at 0° C. was added 12.9 mL (25.8 mmol) of benzylmagnesiumchloride in THF (purchased from Aldrich Chemical) followed by 10 mg(catalyst) of copper (I) iodide. The reaction was stirred at 0° C. for 1h, and at room temperature for 3 h. The reaction was diluted with etherand aqueous NH₄ Cl solution. The organic fraction was washed with waterand brine, dried (MgSO₄) and concentrated to provide 2.70 g of a crudeoil. The oil was purified by flash chromatography (250 g of silica gel)eluting with 8:2 ethyl acetate/hexane to provide 1.10 g (99%) of titlecompound as a colorless oil.

TLC Silica gel (8:2 hexane/ethyl acetate) R_(f) =0.29.

B. (E)-(9-Iodo-5-methyl-5-nonenyl)benzene

A solution of 980 mg (4.22 mmol) of Part A alcohol in 10 mL of methylenechloride and 0.76 mL (5.49 mmol) of triethylamine at 0° C. was treatedwith 0.39 mL (5.07 mmol) of methanesulfonyl chloride dropwise over 0.2h. The reaction mixture was stirred for 1.0 h when it was quenched withsaturated aqueous KHSO₄ solution and diluted with ether. The layers wereseparated and the organic fraction was washed with solutions of NaHCO₃and brine, dried (MgSO₄) and evaporated to provide the mesylate as apale yellow oil.

The crude mesylate was diluted with 100 mL of acetone and treated with3.65 g (24.39 mmol) of NaI at room temperature for 48 h. The mixture wasdiluted with 200 mL of a hexane/water mixture. The organic fraction wasextracted with NaHSO₃, brine, dried (MgSO₄) and concentrated to providea colorless oil. The oil was purified by flash chromatography (50 g ofsilica gel ) eluting with 8:2 ethyl acetate/hexane to provide 1.05 g(76%) of title compound as a colorless oil.

TLC Silica gel (8:2 hexane/ethyl acetate) R_(f) =0.64.

C. (E)-1-(Diethoxyphosphinyl)-6-methyl-10-phenyl-5-decene-1-sulfonicacid, cyclohexyl ester

To a stirred solution of 0.93 g (2.95 mmol) of Example 1A Part Bcompound in 3 mL DMF at -20° C. was added 51 mg (2.13 mmol) of sodiumhydride. After the hydrogen evolution diminished, the reaction wasbrought to RT and stirred for 10 minutes. When hydrogen evolutionsubsided Completely, 0.56 g (1.64 mmol) of Part B iodide was added andthe reaction stirred 24 hours before storing at -80° C. for 30 hours.The reaction was quenched with 10 mL of saturated aqueous ammoniumchloride solution, diluted with ether (150 mL) and water (75 mL). Theaqueous layer was removed and the organics washed with saturated sodiumchloride. The combined aqueous layers were back extracted with ether andthe combined organic fractions dried (over sodium sulfate) andevaporated. The crude material was purified by flash chromatography onsilica gel (60 g), packed, loaded, and eluted with 60:40 hexane/ethylacetate. The pure fractions (#8-18) were combined and concentrated toyield 0.55 g (64%) of title compound as a clear oil.

TLC Silica gel (60:40 hexane/ethyl acetate) R_(f) =0.25.

MS (CI, + ions) m/e 529 (M+H), 546 (M+NH₄).

IR (KBr) 2934, 2858, 1452, 1454, 1260, 1194, 1053, 1024, 928 cm⁻¹.

¹ H NMR (400 MHz, CDCl₃) δ7.18 (t, 2H, J=7.5 Hz) 7.08 (d, 3H, J=7.5 Hz)5.03 (t, 1H, J=7.0 Hz) 4.76 (m, 1H) 4.14 (m, 4H) 3.35 (dt, 1H, J=19.7,6.5 Hz) 2.53 (t, 2H, J=7.7 Hz) 2.05 (m, 2H) 1.95 (m, 5H) 1.77-1.17 (m,16H) 1.50 (s, 3H) 1.28 (t, 6H, J=8.0 Hz) ppm.

D. (E)-6-Methyl-10-phenyl-1-phosphono-5-decene-1-sulfonic acid,tripotassium salt

To a solution of 0.496 g (1.93 mmol) of Part C triester in 10 mLmethanol in a sealable tube was added ammonia gas at 0° C. untilsaturated. The tube was then sealed and heated at 65° C. for 24 hours.The tube was opened and the solution evaporated to a glassy oil whichwas evaporated from toluene two times and dried under high vacuum,leaving an amber oil. The residue was dissolved in 3.5 mL methylenechloride and treated sequentially with 1.53 mL (11.55 mmol) of collidineand 1.78 mL (13.47 mmol) of bromotrimethylsilane bromide. The reactionmass was stirred at RT under argon for 24 hours, at which point anadditional 0.254 mL (13.47 mmol) of collidine and 0.508 mL (3.86 mmol)of bromotrimethylsilane were added. After 45 hours at room temperature,the reaction was quenched with 6.95 mL (6.95 mmol) of 1N KOH andlyophilized. The remainder was purified by MPLC on a column of CHP-20Pgel (2.5 cm diameter×21 cm height), eluting with water (100 mL),followed by a gradient formed by the gradual addition of 400 mLacetonitrile to a reservoir of 350 mL water. Approximately 10 mLfractions were collected. Pure fractions (#30-32) were combined,concentrated to 0.36 g, and passed through a column of 30 g (153 meg) AG50W-XG (K⁺ form) with water. The potassium salt eluted in fractions 1 to4, which were lyophilized, providing a granular powder. The lyophilatewas diluted in 150 μL water and triturated with 2 mL portions of acetonethree times. The product was dried under high vacuum for three days,yielding 259 mg (26%) of title salt as a pale beige powder.

IR (KBr) 3424, 2932, 2857, 1653, 1200, 1080, 966 cm⁻¹.

MS (Ion Spray, + ions) 429 (M-2K+3H), 467 (M-K+2H), 505 (M+H).

¹ H NMR (300 MHz, D₂ O) δ7.25 (m, 5H) 5.25 (t, 1H, J=6.5 Hz) 2.85 (dt,1H, J=19.0, 6.0 Hz) 2.60 (t, 2H, J=8.5 Hz) 2.00 (m, 6H) 1.53 (s, 3H)1.53 (m, 4H) 1.40 (quint, 2H, J=6.4 Hz) ppm.

Anal. Calc'd. for C₁₇ H₂₄ K₃ PO₆ S-2.1 H₂ O: C, 37.64; H, 5.24; P, 5.71;S, 5.91 Found: C, 37.64; H, 5.19; P, 5.34; S, 6.09

EXAMPLE 26

4-(3-Phenylpropyl)-α-phosphonobenzenebutanesulfonic acid, tripotassiumsalt

A. 4-(1-Hydroxy-3-phenyl-2-propynyl)benzoic acid, methyl ester

To a stirred solution of 4.40 mL (40.0 mmol) of phenylpropyne in 30 mLof THF under nitrogen at -75° C. was added a solution of 16 mL (40 mmol)of 2.5M n-butyllithium in hexane over 20 min. The resulting light yellowsolution was warmed to 0° C. and stirred for 30 min. This solution wasadded via syringe to a slurry of 6.25 g (38.0 mmol) of methyl4-formylbenzoate in 30 mL of THF at -30° C. over 20 min. The resultinglight yellow solution was warmed to room temperature and stirred for 30min. The reaction was quenched with saturated ammonium chloridesolution, extracted twice with ether, dried (MgSO₄) and evaporated.Purification by flash chromato-graphy (5×15 cm column, 1:19ether/dichloromethane as elutent) gave title compound as a white solid,mp 48°-50° C., 9.36 g, 88% yield.

B. 4-(3-Phenylpropyl)benzoic acid, methyl ester

A 500 mL Parr vessel was charged with 3.11 g (11.7 mmol) of Part Acompound in 100 mL of methanol and purged with a rapid stream ofnitrogen for 15 min. The solution was treated with 0.5 g of Pearlman'scatalyst (20% Pd(OH)₂ on carbon, 31% H₂ O). This mixture was agitatedfor 16 h at an initial hydrogen pressure of 42 psi. Total hydrogenuptake was 15 psi. The reaction was purged with nitrogen, filteredthrough Celite and evaporated. The oily residue was dissolved indichloromethane, dried (MgSO₄) and filtered to give title compound as acolorless oil, 2.85 g, 97% yield. The material was used without furtherpurification.

C. 4-(3-Phenylpropyl)benzaldehyde

To a stirred solution of 2.80 g (11.0 mmol) of Part B compound in 20 mLof methanol under nitrogen at room temperature was added 22 mL (22 mmol)of 1M NaOH solution. The milky solution was heated to 60° C. for 2 h.The resulting clear solution was cooled and 1M HCl solution was added tobring the reaction mixture to pH 2. The resulting solids were collected,washed with water and dried in vacuo at 60° C. to give 2.55 g (96%) ofthe carboxylic acid of the Part B compound.

This solid was dissolved in 25 mL of dichloromethane under nitrogen and1.4 mL (15 mmol) of oxalyl chloride followed by 0.1 mL of DMF. Theresulting vigorously bubbling solution was stirred for 1 h and thenevaporated. The semi-solid residue was dissolved in 25 mL of benzeneunder nitrogen and 170 mg (0.15 mmol) oftetrakis(triphenylphosphine)palladium was added. To this stirringsolution at room temperature was added 11.1 mL (34 mmol) of tributyltinhydride over 20 min. The solution turns yellow and warms autogenously to40° C. After 1 h, the reaction was treated with 40 mL of 10% aqueouspotassium fluoride and stirred vigorously for 30 min. The reaction masswas filtered, the filtrate diluted with ether, washed with water, andthe organic layer separated, dried (MgSO₄) and evaporated onto 10 g ofsilica gel. Purification by flash chromatography (5×20 cm column, 45:55dichloromethane/hexanes as elutent) gave 2.15 g, 87% yield (84% yieldfrom Part B compound), of title compound as a colorless oil.

D. α-Ethenyl-4-(3-phenylpropyl)benzenemethanol, acetate ester

To a stirred slurry of 11.0 mL (11.0 mmol, 1M in THF) of vinyl magnesiumbromide in 20 mL of THF at -40° C. under argon was added a solution of1.95 g (8.7 mmol) of Part C compound in 10 mL of THF over 20 min. Theresulting pale yellow solution was warmed to room temperature, stirredfor 2 h and then quenched with saturated ammonium chloride solution. Thereaction mixture was extracted twice with ether. The extracts werecombined, dried (MgSO₄) and evaporated. The resulting yellow oil wasdissolved in 20 mL of dichloromethane at room temperature under nitrogenand 2.2 mL (16 mmol) of triethylamine and 1.4 mL (15 mmol) of aceticanhydride were added, followed by 100 mg (0.4 mmol) of DMAP. After 30minutes, the reaction mixture was diluted with ether, washed twice with10% citric acid, once with brine and once with saturated sodiumbicarbonate. The organic phase was dried (MgSO₄) and evaporated onto 10g of silica gel. Purification by flash chromatography (5×25 cm column,2:3 dichloromethane/hexanes as elutent) gave 7.12 g, 92%, of titlecompound as a colorless oil.

E.(E)-1-(Diethoxyphosphinyl)-4-[4-(3-phenylpropyl)phenyl]-3-butene-1-sulfonicacid, 1-methylethyl ester

To a stirred solution of 1.33 g (4.52 mmol) of Part D compound, 2.5 mL(10 mmol, 2.2 equiv.) of bis(trimethylsilyl)acetamide, 2.48 g (9.0 mmol,2.0 equiv.) of Example 11 Part A sulfonate and 125 mg (0.5 mmol) oftriphenyl-phosphine in 20 mL of THF under argon was added 270 mg (0.24mmol) of tetrakis(triphenylphosphine)-palladium. The resulting mixturewas heated to reflux for 30 min. The reaction was cooled, evaporated,diluted with ether and washed once with 10% citric acid and thrice withwater. The organic phase was dried (MgSO₄) and evaporated. Purificationby flash chromatography on silica gel (5×25 cm column) eluted with 2:23ether/dichloro-methane gave title compound as a colorless oil, 1.10 g,55% yield.

F. α-(Diethoxyphosphinyl)-4-(3-phenylpropyl)benzenebutanesulfonic acid,1-methylethyl ester

To an argon-purged solution of 890 mg (1.75 mmol) of Part E compound and100 mg of 10% palladium-on-carbon in 20 mL of ethyl acetate in a 500 mLone-neck round bottom flask was attached a hydrogen-filled rubberbladder of approximately 1 L capacity. The reaction mixture wasvigorously stirred for 16 h, purged with nitrogen, filtered throughCelite and the filtrate evaporated. The oily residue was redissolved indichlormethane, filtered through a 0.75μ filter and re-evaporated togive title compound as a colorless oil, 865 mg, 99% yield. The productwas used without further purification.

G. 4-(3-Phenylpropyl)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt

To a stirred solution of 860 mg (1.7 mmol) of Part F compound in 10 mLof dichloromethane under argon at room temperature was added 700 μL (5.3mmol) of bromotrimethylsilane. After 24 h, the resulting clear solutionwas evaporated at 25° C. and the residue dissolved in 10 mL of THF. Tothis stirred solution was added 560 mg (3.4 mmol) of dried, finelyground potassium iodide and 3 mg (0.01 mmol) of 18-crown-6. Theresulting slurry was heated to reflux for 24 h, evaporated and thenstirred for 1 h with 6 mL (6 mmol) of 1.0M potassium hydroxide solution.The solution was lyophilized and then purified by MPLC (2.5×20 cm columnof Mitsubishi Kasei Sepadbeads HP-20 resin): 1.5 mL fractions, 7 mL/minflow rate, eluted with 200 mL of water and then a gradient prepared from400 mL of water and 450 mL of 2:1 acetonitrile/water). Fractions 38-48were collected and lyophilized to give title salt as a white solid, 640mg, 69% yield.

IR (KBr pellet) 3428, 3084, 2934, 2859, 1659, 514, 1196, 1107, 1084, 966cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ7.10 (m, 9H) 2.76 (dm, 1H, J=17.3 Hz) 2.45 (m,6H) 1.74 (m, 6H) ppm.

Anal. Calc'd for C₂₀ H₁₈ K₃ O₆ PS.1.1 H₂ O: C, 41.77; H, 4.46; P, 5.67;S, 5.87 Found: C, 41.77; H, 4.68; P, 5.46; S,6.08.

MS (FAB, + ions) m/e 565 (M+K), 527 (M+H), 489 (M-K+2H).

EXAMPLE 27

(E,E)-1-(Hydroxymethylphosphinyl)-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, dipotassium salt.

A. Chloromethylphosphinic acid, ethyl ester

To a solution of 15.0 g (98.6 mmol, 1 eq) of diethyl methylphosphonatein 20 mL of dry benzene at room temperature was added 20.5 g (98.6 mmol,1 eq) of phosphorus pentachloride as a solid all at once. The reactionbecame very exothermic and began to reflux. Stirring was discontinuedand the flask was cooled to 0° C. After 5 minutes, the ice bath wasremoved and the reaction mixture was warmed to room temperature andstirred for 2 hours, then heated at reflux for 1 hour. After cooling toroom temperature, the reaction mixture was concentrated. High vacuum(0.1 mmHg) removal of phosphorus oxychloride (POCl₃, a volatileby-product of the reaction; Note 1) and any solvent remnants for 13 hafforded 3.42 g of a cloudy yellow liquid which was used withoutpurification or characterization.

B. (Ethoxymethylphosphinyl)methanesulfonic acid, cyclohexyl ester

To a solution of 8.55 g (48.0 mmol, 1 eq) of Example 1A Part A mesylatein 200 mL of dry THF at -75° C. was added 19.2 mn (48.0 mmol, 1 eq) ofn-butyllithium (2.5M hexane solution) dropwise at a rate that kept thetemperature below -72° C. (addition time 35 min). The resulting clearlight yellow solution was stirred for 10 min at -74° C. A solution of3.42 g of Part A chloride in 20 mL of dry THF was added dropwise at arate that again kept the temperature below -72° C. (addition time 40min). The resulting brown reaction mixture was stirred for 90 min at-74° C. and then quenched by addition of a solution of 2.75 mL (48.0mmol, 1 eq) of glacial acetic acid in 10 mL of THF over 5 min. Thesolution was warmed to room temperature and concentrated. The viscousbrown residue was taken up in dichloromethane (200 mL), washed withwater (100 mL), brine (100 mL), dried (MgSO₄) and concentrated to affordafter high vac removal of solvent remnants 9.26 g of a viscous brownoil. The desired product was isolated by flash chromatography on silicagel (1000 g) eluting initially with ethyl acetate (5 L) followed by 10%ethanol in ethyl acetate (2 L). Fractions (40 mL) containing the cleanproduct were pooled and concentrated to afford 3.91 g of title compoundas a viscous yellow oil (57% assuming starting phosphonyl chloride waspure).

TLC Silica gel (Ethyl acetate): R_(f) 0.35.

C.(E,E)-1-(Ethoxymethylphosphinyl)-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, cyclohexyl ester

To a suspension of 222 mg (5.6 mmol, 2 eq) of sodium hydride (as a 60%mineral oil dispersion) in 1 mL of dry dimethylformamide (DMF) at 0° C.was added dropwise a solution of 1.58 g (5.6 mmol, 2 eq) of Part Bcompound in 3 mL of dry DMF. The vigorously bubbling solution wasstirred for 5 min at 0° C. followed by 30 min at room temperature. Tothe resulting homogeneous brown solution was added a solution of 1.0 g(2.8 mmol, 1 eq) of Example 1 Part C iodide in 3 mL of DMF. After 16 hat room temperature, the reaction was quenched by adding 25 mL of water.The heterogeneous solution was partitioned between ether (100 mL) andbrine (25 mL). The aqueous layer was extracted with ether (4×20 mL) andthe combined organic layers were dried (MgSO₄) and concentrated toafford after high vac (0.25 mmHg) removal of solvent remnants 1.49 g ofcrude product as a light brown oil. The desired product was isolated viaflash chromatography on silica gel (250 g) eluting with 9% isopropanolin hexanes. Fractions (40 mL each) containing clean product were pooledand concentrated to afford 813 mg of title compound (56%) as a lightyellow oil. TLC Silica gel (15% isopropanol in hexanes): R_(f) 0.34.

D.(E,E)-1-(Hydroxymethylphosphinyl)-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, dipotassium salt

Into a solution of 800 mg (1.55 mmol, 1 eq) of Part C compound in 10 mLof dry methanol (MeOH) at 0° C. was bubbled gaseous ammonia until thesolution was saturated. The tube was sealed with a threaded teflon capfitted with an O-ring and heated at 75° C. for 17 h. The volatiles wereremoved in vacuo and the oily residue was co-evaporated twice withtoluene before placing on high vac (0.25 mmHg) for three hours. To theresulting clear yellow oil was added 8 mL of dry CH₂ Cl₂ followed by2.04 mL (15.5 mmol, 10 eq) of dry 2,4,6-collidine. To the resultinglight yellow clear solution was added 2.04 (15.5 mmol, 10 eq) ofbromotrimethylsilane (TMSBr) and the resulting white heterogeneousmixture was stirred at room temperature. After 16 h, the reactionmixture was concentrated and placed on high vac (0.25 mmHg) for 3 h. Theresulting yellow white solid was dissolved by adding 7.3 mL (7.3 mmol,4.7 eq) of 1M potassium hydroxide (pH 12.35), frozen and lyophilized.The light brown lyophilate was dissolved in water and chromatographed ona column of CHP20P (2.5 cm×25 cm) eluting initially with water (150 mL)followed a gradient formed by the gradual addition of acetonitrile (400mL) to a reservoir containing water (400 mL). No fractions (10 mL each)containing clean product by were obtained. The fractions containingapproximately 2% of an impurity (which eluted just before the desiredproduct) were pooled, concentrated and rechromatographed using the sameconditions. Fractions containing clean product by HPLC were concentratedand the reasidual waxy residue was triturated with acetone to afford 274mg of title salt (37%) as a white solid.

TLC Silica gel (7:2:1 n-propanol:ammonium hydroxide:water): R_(f) 0.47.

¹ H NMR (D₂ O, 300 MHz): δ5.09 (t, 1 H, J=6.8 Hz) 5.01 (t, 1H, J=6.9 Hz)4.98 (t, 1H, J=6.8 Hz) 2.75 (dt, 1H, J=15.0, 5.6 Hz) 1.90 (m, 10H) 1.76(m, 2H,) 1.51 (s, 3H) 1.47 (s, 3H) 1.44 (s, 6H₅) 1.43 (m, 2H) 1.21 (d,3H, J=14.3 Hz) ppm.

¹³ C NMR (D₂ O, 75.6 MHz): δ136.7 136.3 133.0 124.8 124.8 124.7 63.0 (d,J_(CP) =81 Hz) 39.4 39.3 29.6 (d, J_(CP) =5 Hz) 27.8 26.9 26.4 26.3 25.317.4 16.0 (d, J_(CP) =98 Hz) 15.7 ppm.

IR (KBr) 2922, 2857, 1213, 1188, 1088, 1034 cm⁻¹.

MS (FAB, + ions ) m/z 483 (M+H), 445 (M+2H-K), 407 (M+3H-2K).

Anal. Calcd. for C₁₉ H₃₃ O₅ PSK₂ : C, 47.28; H, 6.89; P, 6.42; S, 6.64Found: C, 47.30; H, 6.92; P, 6.04; S, 6.94

EXAMPLE 28

(E,E)-1-(Hydroxyphosphinyl)-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, dipotassium salt

A. (E,E)-6,10,14-Trimethyl-5,9,13-pentadecxatriene-1-sulfonic acid,ethyl ester

n-Butyllithium (11.1 mL, 2.5M in hexanes, 27.8 mmol) was added dropwiseover 15 min to a solution of ethyl methanesulfonate (5.17 g, 41.7 mmol)in THF (50 mL) at -78° C. under argon. The clear colorless reactionmixture was stirred at -78° C. for 20 min, whereupon a solution ofExample 1 Part C iodide (5.00 g, 13.9 mmol) in THF (10 mL) was addeddropwise over 10 min. The reaction was warmed to -60° C. (internaltemperature) and stirred at that temperature for 1.5 h. The reaction wasthen warmed to -20° C. over 2 h, then quenched by addition of saturatedNH₄ Cl (20 mL). Diethyl ether (300 mL) was added, and the organic layerwas washed with water (2×50 mL) and brine (10 mL), then dried overMgSO₄. Evaporation gave a yellow oil, which was purified by flashchromatography on silica gel (200 g) eluting with a step gradient of5:95 to 8:92 EtOAc/hexane to provide title compound (3.61 g, 73%) as acolorless oil.

B.(E,E)-1-(Ethoxyphosphinyl)-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, ethyl ester

n-Butyllithium (2.7 mL, 2.5M in hexanes, 6.7 mmol) was added dropwise toa solution of Part A compound (2.00 g, 5.62 mmol) in THF (15 mL) at -78°C. under argon. The yellow reaction was stirred at -78° C. for 30 min,whereupon diethyl chlorophosphite (2.4 mL, 16.9 mmol) was added rapidlyin one portion. The colorless reaction was stirred at -78° C. for 1 h,then allowed to warm to RT over 2.5 h. The reaction was diluted withanhydrous diethyl ether (50 mL). Water (10 mL) was then added, and theresultant biphase mixture was stirred vigorously at RT for 1 h. Theaqueous layer was removed, and the organic layer was washed with water(10 mL) and brine (15 mL), then dried over MgSO₄. Evaporation gave acolorless oil, which was purified by flash chromatography on CC7buffered silica gel (250 g) eluting with a step gradient of 25:75 to35:65 to 45:55 EtOAc/hexane to give title compound (2.07 g, 82%) as acolorless oil as a 1:1 mixture of diastereomers.

C.(E,E)-1-(Hydroxyphosphinyl)-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, dipotassium salt

Potassium iodide (317 mg, 1.91 mmol) was added to a solution of Part Bcompound (816 mg, 1.82 mmol) in acetone (10 mL) under argon. As themostly insoluble potassium iodide reacted, the product precipitated outof the reaction mixture. The white heterogeneous reaction was stirred atRT overnight, concentrated in vacuo, then pumped at high vacuum to givea white solid.

The crude sulfonate salt was dissolved in 1N KOH (3.6 mL, 3.6 mmol),then chromatographed on CHP-20P gel (2.5×20 cm column) eluting withwater followed by a gradient created by the gradual addition ofacetonitrile to a reservoir of water. The product fractions wereconcentrated in vacuo to give an opaque white gum. Acetone (2 mL) wasadded and the product was precipitated out as a solid. The solid wasfiltered, washed with acetone (2×5 mL), then pumped at high vacuum togive title salt (507 mg, 60%) as a white solid.

TLC (silica gel) (7:2:1 n-propanol/NH₄ OH/H₂ O): R_(f) =0.43

IR (KBr) 2928, 2857, 2288, 1202, 1094 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ7.02 (d, 1H, J=548 Hz) 5.12 (t, 1H, J=6.8 Hz)5.06 (t, 1H, J=6.8 Hz) 5.04 (t, 1H, J=6.8 Hz) 2.85 (dt, 1H, J=6.4, 13.7Hz) 2.03-1.85 (m, 10H) 1.78 (m, 2H) 1.54 (s, 3H) 1.49 (s, 3H) 1.47 (s,6H) 1.44 (m, 2H) ppm.

¹³ C NMR (D₂ O, 100 MHz) δ136.53 135.96 132.67 124.60 124.55 124.4762.42 (d, J=81 Hz) 39.29 39.18 28.41 (d, J=6 Hz) 27.56 26.23 26.19 25.1524.93 17.24 15.55 ppm.

MS (ES, + ions) m/z 393 (M+3H-2K), 410 [(M+2H-2K)+NH₄ ], 427[(M+2H-2K)+NH₃ +NH₄ ], 431 (M+2H-K), 448 [(M+2H-K)+NH₃ ], 469 (M+H).

Anal. Calc'd for C₁₈ H₃₁ K₂ O₅ PS: C, 46.13; H, 6.67; P, 6.61; S, 6.84.Found: C, 46.18; H, 6.68; P, 6.28; S, 7.17.

EXAMPLE 29

4-(Phenylmethyl)-α-phosphonobenzenebutanesulfonic acid, tripotassiumsalt

A. 1-Bromo-4-(phenylmethyl)benzene

To a stirred solution of 21 mL (42 mmol, 2.0M in THF) of benzylmagnesiumchloride at room temperature under nitrogen was added a solution of 6.80g (50.0 mmol) of thrice-fused zinc chloride, in 50 mL of THF. Theresulting tan slurry was stirred for 1 hour. To this slurry was added10.0 g (35.3 mmol) 1-bromo-4-iodobenzene and 450 mg (0.4 mmol) oftetrakis(tri-phenylphosphine)palladium in 30 mL of THF. The reaction wasstirred at room temperature for 16 hours and then quenched with 50 mL of2M hydro-chloric acid. The mixture was extracted thrice with hexanes,the extracts combined, washed once with saturated sodium bicarbonatesolution and once with 10% sodium thiosulfate. The organic extract wasdried (MgSO₄) and evaporated. The crude product was purified by flashchromatography on silica gel (5×25 cm column, hexanes as elutent) togive 7.05 g (80%) of title compound as a colorless oil.

B. α-Ethenyl-4-(phenylmethyl)benzenemethanol acetate ester

To a stirred solution of 2.47 g (10.0 mmol) of Part A compound in 30 mLof THF at -60° C. under nitrogen was added a solution of 12 mL (20 mmol,1.7M in pentane) of t-butyllithium over 20 minutes. The resulting deepred solution was warmed to 0° C. and stirred for 30 min. To theresulting solution was added 1.0 mL (18 mmol) of freshly distilledacrolein over 5 min. The resulting light yellow solution was stirred for30 min, quenched with saturated ammonium chloride. The mixture wasextracted twice with ether, dried (MgSO₄) and evaporated to give acolorless oil.

The solid was dissolved in 30 mL of dichloromethane, stirred undernitrogen at room temperature and treated with 2.2 mL (15.8 mmol) oftriethylamine, 1.3 mL (14 mmol) of acetic anhydride and 50 mg (0.4 mmol)of DMAP. After 30 min, the reaction mixture was evaporated, redissolvedin ether and washed once with 10% citric acid solution, once with brineand once with saturated sodium bicarbonate solution. The organic phasewas dried (MgSO₄) and evaporated. The crude product was purified byflash chromatography on silica gel (5×15 cm column, 1:1dichloromethane/hexanes as elutent) to give 2.51 g (94% from Part Acompound) of title compound as a colorless oil.

C. (E)-1-(Diethoxyphosphinyl)-4-[4-(phenylmethyl)phenyl]-3-butene-1-sulfonic acid, cyclohexyl ester

To a stirred solution of 1.45 g (5.44 mmol) of Part B compound, 2.5 mL(11.7 mmol, 2.15 equivalents) of bis(trimethylsilyl)acetamide, 3.14 g(10.0 mmol, 1.8 equivalents) of Example 1A Part B sulfonate and 270 mg(1.0 mmol) of triphenylphosphine in 15 mL of THF under nitrogen wasadded 600 mg (0.53 mmol) of tetrakis(triphenylphosphine)palladium. Theresulting mixture was heated to reflux for 1 h. The reaction was cooledand evaporated and pumped at room temperature @0.2 Torr for 24 hours.The residue was diluted with dichloromethane and evaporated onto 5 g ofsilica gel. Purification by flash chromatography on silica gel (5×25 cmcolumn) eluted with 1:13 ether/dichloromethane gave title compound as ayellow oil, 1.65 g, 58% yield.

D. α-(Diethoxyphosphinyl)-4-(phenylmethyl) benzenebutanesulfonic acid,cyclohexyl ester

To a nitrogen-purged slurry of 1.15 g (2.2 mmol) of Part C compound and120 mg of 10%Pd/C in 50 mL of ethyl acetate in a 200 mL one-neck roundbottom flask was attached a hydrogen-filled rubber bladder ofapproximately 1 L capacity. The reaction mixture was vigorously stirredfor 16 h, purged with nitrogen, filtered through Celite and the filtrateevaporated.. The oily residue was redissolved in dichloromethane,filtered through a 0.75μ filter and re-evaporated to give title compoundas a colorless oil, 1.15 g, 99% yield. The product was used withoutfurther purification.

E. 4-(Phenylmethyl)-α-phosphonobenzenebutanesulfonic acid. tripotasisumsalt

To a stirred solution of 1.15 g (2.20 mmol) of Part D compound in 10 mLof dichloromethane under nitrogen at room temperature was added 1.0 mL(7.5 mmol) of bromotrimethylsilane. After 24 h, the resulting clearsolution was evaporated at 25° C. and the residue dissolved in 10 mL ofTHF. To this stirred solution was added 830 mg (5 mmol) of dried, finelyground potassium iodide and 6 mg (0.02 mmol) of 18-crown-6. Theresulting slurry was heated to reflux for 20 h, evaporated and thenstirred for 1 h with 7 mL (7 mmol) of 1M potassium hydroxide solution.The solution was lyophilized and then purified by MPLC (2.5×20 cm columnof Mitsubishi Kasei Sepadbeads CHP20P resin): 11.5 mL fractions, 7mL/min flow rate, eluted with water. Fractions 29-55 were collected andlyophilized to give title salt as a white solid, 840 mg, 76% yield.

IR (KBr pellet) 3426, 3063, 2934, 2864, 1636, 1198, 1074, 966 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) 7.16 (m, 5H) 7.08 (d, 2H, J=8.3, H₃) 7.05 (d,2H, J=8.3, H₂) 3.78 (s, 2H) 2.72 (ddd, 1H, J=3.9, 6.4, 18 Hz) 2.45 (m,2H) 1.75 (m, 4H) ppm.

MS (FAB, + ions) m/e 536 (M+K), 499 (M+H), 461 (M-K+2H).

Anal. Calc'd for C₁₇ H₁₈ K₃ PSO₆.1H₂ O: C, 39.33; H, 3.94; P, 5.97; S,6.18 Found: C, 39.33; H, 4.06; P, 5.71; S, 5.89.

EXAMPLE 30

(E,E)-1-[Hydroxy(methoxymethyl)phosphinyl)-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, dipotassium salt

A. (Methoxymethyl)phosphonic acid, diethyl ester

To a sample of 17.90 mL (0.104 mol) of triethylphosphite at -78° C.under argon was added, dropwise 8.50 mL (0.104 mol) of bromomethylmethyl ether. The mixture slowly warmed to RT and stirred for 24 h, whenit was fractionally distilled 100° C., 5 mm) to provide 16.22 g (98%) oftitle compound as a pale yellow oil.

TLC Silica Gel (Ethyl acetate) R_(f) =0.50.

B. Chloro(methoxymethyl)phosphinic acid, ethyl ester

To a solution of 5.0 g (27.6 mmol, 1 eq) of Part A compound in 5 mL ofdry benzene at 0° C. was added 5.75 g (27.6 mmol, 1 eq) of phosphoruspentachloride as a solid in one portion. The resulting heterogeneoussolution was stirred at 0° C. for 5 min, then warmed to room temperatureand stirred for 5 min. The resulting homogeneous solution was heated atreflux for 1 h, cooled to room temperature and concentrated. The residuewas co-evaporated twice with benzene followed by exposure to high vacuum(0.25 mmHg) for 1 h to afford 4.52 g (95%) of title compound as a yellowliquid which was used in the next step without purification.

C. [Ethoxy(methoxymethyl)phosphinyl]methanesulfonic acid, cyclohexylester

To a solution of 9.84 g (55.2 mmol, 2.1 eq) of Example 1A Part Amesylate compound in 200 mL of dry tetrahydrofuran (THF) at -75° C.(internal temperature) was added dropwise via syringe 22.1 mL (55.2mmol, 2.1 eq) of a 2.5M n-butyllithium solution in hexanes at a ratethat kept the temperature below -71° C. (over 40 min). The , resultingsolution was stirred for 5 min at -75° C. A solution of 4.52 g (26.2mmol, 1 eq) of freshly prepared Part B compound in 20 mL of THF wasadded dropwise at a rate to keep the temperature below -71° C. (over 30min) and the resulting light brown solution was stirred at -75° C. for 1h. The reaction was quenched by addition of a solution of 3.16 mL (55.2mmol, 2.1 eq) of glacial acetic acid in 15 mL of THF over 5 min, thenallowed to warm to room temperature. The solution was concentrated andthe viscous residue was taken up in dichloromethane (250 mL), washedwith water (100 mL), brine (100 mL), dried (MgSO₄) and concentrated toafford 12.4 g of a light brown oil. The desired product was isolated byflash chromatography on silica gel (250 g) eluting with ethyl acetate.The fractions containing product by TLC were combined and concentratedto afford a solid which was contaminated by an unknown impurity asevidenced by extraneous peaks in the ¹ H NMR spectrum. The solid wasrecrystallized from hexanes/chloroform to afford 5.04 g (61%) of thetitle compound as a white solid, m.p. 78.5°-79.5 C.

TLC Silica gel (ethyl acetate) R_(f) 0.40.

D.(E,E)-1-[Ethoxy(methoxymethyl)phosphinyl]-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, cyclohexyl ester

To a suspension of 222 mg (5.6 mmol, 2 eq) of sodium hydride (as a 60%dispersion in mineral oil) in 1 mL of dry dimethylformamide (DMF) at 0°C. was added a solution of 1.74 g (5.6 mmol, 2 eq) of Part C compound in4 mL of DMF dropwise over 10 min. The bubbling heterogeneous mixture wasallowed to warm to room temperature and stir for 30 min. To theresulting homogeneous solution was added a solution of 1.0 g (2.8 mmol,1 eq) of Example 1 Part C iodide in 3 mL of DMF. After 20 h, thereaction was diluted with brine (25 mL). The resulting cloudy solutionwas extracted with ether (1×100 mL, 3×15 mL), dried (MgSO₄) andconcentrated to afford 1.64 g of a yellow oil. The desired product wasisolated by flash chromatography on silica gel (250 g) eluting with 40%ethyl acetate in hexanes. Fractions containing clean product by TLC werepooled and concentrated to afford 801 mg.(52%) of title compound as aviscous yellow oil.

TLC Silica gel (1:1 ethyl acetate:hexanes): R_(f) 0.23.

E.(E,E)-1-[Hydroxy(methoxymethyl)phosphinyl)-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, dipotassium salt

To a solution of 600 mg of Part D compound in 12 mL of dry methanol am0° C. was introduced ammonia until the solution was saturated. The tubewas sealed with a threaded teflon cap fitted with an O-ring and heatedat 75° C. for 16 h. The volatiles were removed in vacuo and the oilyresidue was co-evaporated twice with toluene before placing on high vac(0.25 mmHg) for three hours. To the resulting clear yellow oil was added7 mL of dry CH₂ Cl₂ followed by 806 μL (6.1 mmol, 4.5 eq) of dry2,4,6-collidine. To the resulting light yellow clear solution was added1.25 mL (9.5 mmol, 7 eq) of bromotrimethylsilane (TMSBr) and theresulting white heterogeneous mixture was stirred at room temperature.After 21 h, the reaction mixture was concentrated and placed on high vac(0.25 mmHg) for 30 min. The resulting yellow white solid was dissolvedby adding 7.0 mL (7.0 mmol, 5.2 eq) of 1M potassium hydroxide, and theresulting solution was frozen and lyophilized. The light brownlyophilate was dissolved in water and chromatographed on a column ofCHP20P (2.5 cm×25 cm) eluting initially with water (150 mL) followed agradient formed by the gradual addition of a 63% solution ofacetonitrile in water (400 mL) to a reservoir containing water (400 mL).No fractions (10 mL each) containing clean product by HPLC wereobtained. The fractions containing approximately 2% of an impurity(which eluted just before the desired product) were pooled, concentratedand rechromatographed using a step gradient. After eluting with water(150 mL) the column was eluted with 15% acetonitrile in water (300 mL)followed by 20% acetonitrile in water (500 mL). Fractions containingpure product by HPLC were concentrated and the residual waxy residue wastriturated with acetone to afford 245 mg of title salt (35%) as a whitesolid.

TLC Silica gel (7:2:1 n-propanol:ammonium hydroxide:water): R_(f) 0.42.

¹ H NMR (D₂ O, 300 MHz): δ5.06 (t, 1H, J=6.8 Hz) 4.98 (t, 1H, J=6.9 Hz)4.96 (t, 1H, J=7.2 Hz) 3.56 (dd, 1H, J=12.9, 6.9 Hz) 3.40 (dd, 1H,J=12.9, 7.5 Hz) 3.23 (s, 3H) 2.92 (m, C₁₈) 1.83 (m, 12H) 1.49 (s, 3H)1.46 (s, 3H) 1.43 (m, 2H) 1.41 (s, 6H)ppm.

¹³ C NMR (D₂ O, 75.6 MHz): δ136.3 135.7 132.3 124.6 70.9 (d, J_(CP) =116Hz) 60.8 (d, J_(CP) =12 Hz) 59.9 (d, J_(CP) =81 Hz) 39.5 39.4 29.5 (d,J_(CP) =5 Hz) 27.7 26.5 26.4 26.3 (d, J_(CP) =4 Hz) 25.3 17.4 15.7 ppm.

IR (KBr): 3437, 2926, 1449, 1200, 1076, 1030 cm⁻¹.

MS (FAB, + ions) m/z 551 (M+K), 513 (M+H).

Anal. Calc'd for C₂₀ H₃₅ O₆ PSK₂.0.55 H₂ O: C, 45.96; H, 6.96; P, 5.93;S, 6.13 Found: C, 45.96; H, 6.80; P, 5.54; S, 6.50

EXAMPLE 31

(E,E)-1-[Hydroxy(hydroxymethyl)phosphinyl)-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, dipotassium salt

Potassium iodide (370 mg, 2.23 mmol) was added to a solution of Example28 Part B compound (950 mg, 2.12 mmol) in acetone (10 mL) under argon.As the mostly insoluble potassium iodide reacted, the productprecipitated out of the reaction mixture. The white heterogeneousreaction was stirred at RT overnight, concentrated in vacuo, then pumpedat high vacuum to give a white solid.

A heterogeneous mixture of the sulfonate salt paraformaldehyde (254 mg,8.48 mmol), and diisopropylethylamine (184 mL, 1.06 mmol) in absoluteethanol (7 mL) was heated at 60° C. under argon. After 15 min, thereaction went from milky white to clear and colorless. After 7 h at 60°C., the reaction was allowed to cool to RT. The reaction wasconcentrated in vacuo, then pumped at high vacuum to give a whitesemi-solid.

Aqueous KOH (6.4 mL, 1N, 6.4 mmol) was added to the mono-ester preparedabove. The initially white foamy dispersion was stirred at RT underargon overnight, after which time the reaction was clear and colorless.The reaction mixture was chromatographed on CHP20P gel (2.5×20 cmcolumn) eluting with water followed by a gradient created by the gradualaddition of acetonitrile to a reservoir of water. The product fractionswere concentrated in vacuo to give an opaque white gum. Acetone (5 mL)was added and the product was precipitated out as a solid. The solid wasfiltered, washed with acetone (3×5 mL), then pumped at high vacuum togive the title product (520 mg, 49%) as a white solid.

TLC (silica gel) (7:2:1 n-propanol/NH₄₀ H/H₂ O): R_(f) =0.36

IR (KBr) 3430, 2926, 1636, 1449, 1204, 1078, 1024 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ5.12 (t, 1H, J=6.6 Hz) 5.05 (t, 1H, J=6.8 Hz)5.03 (t, 1H, J=7.7 Hz) 3.76 (dd, 1H, J=4.3, 14.4 Hz) 3.53 (dd, 1H,J=6.6, 14.4 Hz) 2.98 (ddd, 1H, J=4.7, 6.8, 13.3 Hz) 1.88 (m, 10H) 1.75(m, 2H) 1.55-1.35 (m, 2H) 1.53 (s, 3H) 1.48 (s, 3H) 1.46 (s, 6H,) ppm.

¹³ C NMR (D₂ O, 100 MHz) δ136.35 135.78 132.37 124.56 60.65 (d, J=109Hz) 60.49 (d, J=78 Hz) 39.34 39.24 29.30 (d, J=6 Hz) 27.69 26.35 26.2826.10 25.17 17.24 15.56 ppm.

Mass Spec (FAB, + ions) m/z 499 (M+H), 537 (M+K).

Anal. Calc'd for C₁₉ H₃₃ K₂ O₆ PS: C, 45.76; H, 6.67; P, 6.21; S, 6.43.Found: C, 45.41; H, 6.92; P, 6.47; 6.77.

EXAMPLE 32

(E,E)-7,11,15-Trimethyl-2-phosphono-6,10,14-hexadecatriene-2-sulfonicacid, tripotassium salt

A.(E,E)-7,11,15-Trimethyl-2-(diethoxyphosphinyl)-6,10,14-hexadecatriene-2-sulfonicacid, cyclohexyl ester

To a suspension of 47 mg (1.2 mmol, 1.1 eq) of sodium hydride (as a 60%mineral oil dispersion) in 1 mL of dry DMF at 0° C. was added a solutionof 580 mg (1.1 mmol, 1 eq) of Example 1A Part C compound in 2 mL of DMFover 1 min. The bubbling solution was allowed to warm to RT and stirredfor 30 min. To the resulting yellow homogeneous solution of anion at RTwas added 264 μL (4.2 mmol, 4 eq) of methyl iodide over 1 min. After 16h, the turbid yellow reaction mixture was diluted with ether (100 mL)and washed with brine (50 mL). The aqueous layer was extracted withether (2×15 mL) and the combined organic layers were dried (MgSO₄) andconcentrated to afford 583 mg of a light yellow cloudy oil. ¹ H NMR ofthe crude oil indicated no unalkylated starting material was present.The desired product was isolated via flash chromatography on silica gel(75 g) eluting with 35% ethyl acetate in hexanes. Fractions containingthe desired product by TLC were pooled and concentrated to afford 418 mg(68%) of title compound as a clear viscous oil.

TLC Silica gel (10% ether in CH₂ Cl₂): R_(f) 0.46.

B. (E,E)-7,11,15-Trimethyl-2-phosphono-6,10,14-hexadecatriene-2-sulfonicacid, tripotassium salt

To a solution of 408 mg of Part A compound in 8 mL of dry methanol at 0°C. was introduced ammonia until the solution was saturated. The tube wassealed with a threaded teflon cap fitted with an O-ring and heated at75° C. for 17 h. The volatiles were removed in vacuo and the oilyresidue was co-evaporated twice with toluene before placing on high vac(0.25 mmHg) for three hours. To the resulting clear yellow oil was added4 mL of dry CH₂ Cl₂ followed by 769 μL (5.8 mmol, 8 eq) of dry2,4,6-collidine. To the resulting light yellow clear solution was added768 μL (5.8 mmol, 8 eq) of bromotrimethylsilane (TMSBr) and theresulting white heterogeneous mixture was stirred at room temperature.After 84 h, the reaction mixture was concentrated and placed on high vac(0.25 mmHg) overnight. The resulting yellow white solid was dissolved byadding 5.0 mL (5.0 mmol, 6.8 eq) of 1M potassium hydroxide (pH 12.45)and 5 mL of water and the resulting solution (pH 12.35) was frozen andlyophilized. The light brown lyophilate was dissolved in water andchromatographed on a column of CHP20P (2.5 cm×25 cm) eluting initiallywith water (150 mL) followed a gradient formed by the gradual additionof acetonitrile (400 mL) to a reservoir containing water (400 mL).Fractions (10 mL each) were collected and analyzed by HPLC (Method 8).One fraction contained material ≧98% pure. This fraction wasconcentrated, taken up in a minimum volume of water, filtered andprecipitated using acetone. The resulting solid was dryed on high vac toafford 134 mg of an off-white solid which did not pass elementalanalysis. The >95% material from the column above was rechromatographedon CHP20P under isocratric conditions with 20% acetonitrile in water.Fractions containing ≧98% material were combined with the >98% materialobtained from the first column, dissolved in water and concentrated. Theresulting glassy solid was triturated with acetone to afford, after highvacuum removal of the acetone remnants, 94 mg title salt in the form ofan off-white solid (24%).

TLC Silica gel (5:4:1 n-propanol:ammonium hydroxide:water): R_(f) 0.24.

¹ H NMR (D₂ O, 300 MHz): δ5.08 (m, 1H) 4.98 (m, 1H) 4.95 (m, 1H) 1.86(m, 12H) 1.49 (s, 3H) 1.45 (s, 3H) 1.43 (m) 1.42 (s, 6H) 1.28 (d, J=13.6Hz) ppm.

¹³ C NMR (D₂ O, 75.6 MHz): δ136.2 135.8 132.3 125.1 124.7 62.3 (d,J_(CP) =126 Hz) 39.5 39.4 34.2 28.8 26.5 26.4 25.3 24.9 (d, J_(CP) =3Hz) 18.2 17.4 15.8 15.7 ppm.

IR (KBr): 3434, 2928, 1452, 1202 cm⁻¹.

MS (FAB, + ions) m/z 499 (M+2H-K), 521 (M-K+Na+H), 537 (M+H).

Anal. Calc'd for C₁₉ H₃₂ O₆ PSK₃.0.5 H₂ O: C, 41.81; H, 6.09; P, 5.67Found: C, 42.20; H, 6.41; P, 4.94.

EXAMPLE 33

4'-(2-Methyl-1-propenyl)-α-phosphono[1,1'-biphenyl]-4-butanesulfonicacid, tripotassium salt

A. 1-Bromo-4-(2-methyl-1-propenyl)benzene

To a stirred slurry of 17.29 g (40.0 mmol) ofisopropyltriphenylphosphonium iodide and 500 mg (2 mmol) of 18-crown-6in 100 mL of THF under nitrogen at 5° C. was added 4.50 g (40.0 mmol) ofpotassium t-butoxide over 5 min. the resulting deep red-orange slurrywas stirred 10 min and then a solution of 6.50 g (35.0 mmol)4-bromobenzaldehyde in 40 mL of THF was added at a rate to keep thetemperature below +10° C. The resulting bright yellow slurry was stirredfor 20 min and then poured into 300 mL of hexanes. The solids werefiltered off and the filtrate evaporated. This residue was purified byflash chromatography (5×15 cm column) and eluted with hexanes to provide5.66 g (77%) of title bromide as a colorless oil.

TLC Silica gel (hexanes) R_(f) =0.32.

¹ H NMR (CDCl₃, 270 MHz) δ7.40 (d, 2H, J=8.4 Hz) 7.05 (d, 2H, J=8.4 Hz)6.17 (s, 1H) 1.88 (s, 1H) 1.81 (s, 1H) ppm.

Anal. Calc'd for C₁₀ H₁₁ Br: C, 56.90; H, 5.25 Found: C, 56.83; H, 5.22.

MS (CI--NH₃, -ions) m/e 209 (M-H).

B. 4'-(2-Methyl-1-propenyl) [1,1-biphenyl]-4-carboxylic acid, methylester

To a stirred solution of 52 mL (88.4 mmol, 1.7M in pentane) oft-butyllithium at -78° C. under argon was added a solution of 7.92 g(37.5 mmol) of Part A bromide in 15 mL of THF over 10 minutes. Theresulting deep red slurry was stirred for 1 hour, warmed to -22° C. anda solution of 6.16 g (45.2 mmol) of thrice-fused zinc chloride in 40 mLof THF was added over 20 minutes. The light yellow, faintly turbidsolution was stirred for 1 hour and then cannula ted into a stirredsolution of 7.04 g (26.9 mmol) of methyl 4-iodobenzoate and 600 mg (0.52mmol) of tetrakis(triphenylphosphine)palladium in 30 mL of THF at -22°C. under argon. After the addition was complete, the reaction was warmedto room temperature and stirred for 16 hours. The reaction mixture wasdiluted with ether, washed successively with 1M hydrochloric acid,saturated sodium bicarbonate and saturated sodium sulfite solution. Theorganic extract was dried (MgSO₄) and evaporated to give a dark brownsolid. Recrystallization from methanol gave title ester as a lightyellow solid, mp 66°-68° C., 6.13 g, 86% yield.

C. 4'-(2-Methyl-1-propenyl) [1,1'-biphenyl]-4-methanol

To a stirred solution of 3.00 g (11.3 mmol) of Part B ester in 10 mL ofTHF at room temperature under nitrogen was added 6.0 mL of lithiumaluminum hydride solution (1.0M in THF, 6.0 mmol). After 1 hour, thereaction was quenched with 1 mL of brine and then sufficient 1Mhydrochloric acid to bring the solution to pH 1. The resulting mixturewas extracted twice with ether, the combined extracts washed withsaturated sodium bicarbonate solution, dried (MgSO₄) and evaporated.Purification by flash chromatography on silica gel (5×10 cm column, 3:97ether/dichloromethane as elutent) gave title alcohol as a colorless oil,2.42 g, 90% yield.

D. 4-(Bromomethyl)-4'-(2-methyl-1-propenyl) [1,1'-biphenyl]

To a stirred solution of 2.82 g of triphenylphosphine (8.4 mmol) and2.33 g (9.79 mmol) of Part C alcohol in 30 mL of dichloromethane underargon at -40° C. was added 1.92 g (11.7 mmol) of N-bromosuccinimide over20 minutes. After 1 hour, the reaction mixture was evaporated onto 10 gof silica gel., Purification by flash chromatography on silica gel (5×20cm column, 12% CH₂ Cl₂ in hexanes as the elutent) gave title bromide asa colorless oil, 2.75 g, 93% yield.

E. 4'-(2-Methyl-1-propenyl) [1,1-biphenyl]-4-propanoic acid,1,1-dimethylethyl ester

To a stirred solution of 1.01 mL (7.2 mmol) of diisopropylamine in 15 mLof THF at -5° C. under argon was added 2.8 mL (7.0 mmol, 2.5M in hexane)of n-butyllithium at a rate to keep the temperature below 0° C. Afterstirring the resulting pale yellow solution for 15 minutes, 3.0 mL (17mmol) of hexamethylphosphoramide was added. After an additional 15minutes, the deep yellow solution was cooled to -78° C. and 0.98 mL (7.2mmol) of t-butyl acetate was added over the course of 5 minutes. Thesolution was stirred for 30 minutes and then a solution of 1.75 g (5.8mmol) of Part D bromide in 10 mL of THF was added over 5 minutes. Thereaction mixture was stirred for 8 hours at -78° C., quenched with 10%citric acid solution and extracted twice with ether. The extracts werecombined, washed twice with water, once with saturated sodiumbicarbonate solution, dried (MgSO₄) and evaporated. Purification byflash chromatography on silica gel (5×20 cm column, 1:1hexanes/dichloromethane as elutent) gave title ester as a white foamysolid, 1.85 g, 95% yield.

F. 4'-(2-Methyl-1-propenyl) [1,1'-biphenyl]-4-propanol

To a stirred solution of 1.08 g (3.20 mmol) of Part E ester in 5 mL ofTHF at room temperature under nitrogen was added 2.0 mL of lithiumaluminum hydride solution (1.0M in THF, 2.0 mmol). The reaction washeated to reflux for 1 hour, quenched with 1 mL of brine and thensufficient 1M hydrochloric acid to bring the solution to pH 1. Theresulting mixture was extracted twice with ether, the combined extractswashed with saturated sodium bicarbonate solution, dried (MgSO₄) andevaporated. The oily residue was passed through a 2 cm high pad ofsilica gel, eluting with dichloromethane to give title alcohol as awhite solid, 0.824 g, 97% yield.

G. 4-(3-Iodopropyl)-4'-(2-methyl-1-propenyl) [1.1'-biphenyl]

To a stirred solution of 813 mg (3.05 mmol) of Part F alcohol, 882 mg(3.36 mmol) of triphenylphosphine and 440 mg (6.4 mmol) of imidazole in20 mL of THF was added a solution of 813 mg (3.2 mmol) of iodine in 10mL of THF over 20 min. After 10 min, the light yellow reaction mixturewas diluted with hexanes and washed once each with 10% sodium bisulfitesolution, water and brine. The organic layer was dried (MgSO₄) andevaporated onto 5 g silica gel. Purification by flash chromatography onsilica gel (5×5 cm column) eluted with dichloromethane gave titleiodide, 1.11 g (97%) as a white solid, mp 58°-61° C.

H. 4'-(2-Methyl-1-propenyl)-α-phosphono[1,1'-biphenyl]-4-butanesulfonicacid, cyclohexyl ester

To a stirred slurry of 85 mg (2.1 mmol, 60% mineral oil dispersion) ofsodium hydride in 3 mL, of DMF under argon at -10° C. was added asolution of 670 mg (2.4 mmol, 1.3 equiv.) of Example 1A Part B compoundin 1 mL of DMF. After addition was complete, the reaction was warmed toroom temperature and stirred for 30 min. To the resulting solution wasadded a solution of 700 mg (1.86 mmol) of Part G compound in 1 mL ofDMF. The reaction was stirred for 16 h, diluted with ether and washedonce with 10% citric acid and thrice with water. The organic phase wasdried (MgSO₄) and evaporated. Purification by flash chromatography onsilica gel (5×20 cm column) eluted with 1:24 ether/dichloromethane gavetitle salt as a colorless oil, 610 mg, 62% yield.

I. 4'-(2-Methyl-1-propenyl)-α-phosphono[1,1'-biphenyl]-4-butanesulfonicacid, tripotassium salt

A solution of 500 mg (0.89 mmol) of Part H ester in 15 mL of methanolunder argon at room temperature was saturated with ammonia gas. Theflask containing the reaction mixture was sealed and heated to 75° C.After 16 h, the reaction was cooled to room temperature and evaporatedunder dry conditions. The residue was dissolved in 10 mL ofdichloromethane and 0.59 mL (4.5 mmol) of 2,4,6-collidine and then 940mL (7.1 mmol) of bromotrimethylsilane was added. After 24 h, theresulting clear solution was evaporated at 25° C. and then stirred for 1h with 8 mL (4 mmol) of 0.5M potassium hydroxide solution. The solutionwas lyophilized and then purified by MPLC (2.5×20 cm column ofMitsubishi Kasei Sepadbeads HP-20 resin): 11.5 mL fractions, 7 mL/minflow rate, eluted with water and then a gradient prepared from 400 mL ofwater and 450 mL of 2:1 acetonitrile/water). Fractions 39-48 werecollected and lyophilized to give title salt as a white solid, 310 mg,62% yield.

IR (KBr pellet) 3403, 2967, 2932, 1653, 1497, 1184, 1051, 966 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ7.45 (d, 2H, J=8.1 Hz) 7.44 (d, 2H, J=8.1 Hz)7.25 (d, 2H, J=8.1 Hz) 7.19 (d, 2H, J=8.1 Hz) 6.17 (s, 1H) 2.78 (dt, 1H,J=5, 18 Hz) 2.54 (m, 2H) 1.77-1.91 (m, 4H) 1.74 (s, 3H) 1.69 (s, 3H)ppm.

Anal. Calc'd for C₂₀ H₂₂ K₃ O₆ PS.1.5 H₂ O: C, 42.46; H, 4.45; P, 5.47;S, 5.67 Found: C, 42.35; H, 4.80; P, 5.20; S, 6.06.

Mass Spec (FAB, + ions) m/e 577 (M+K), 539 (M+H), 501 (M-K+2H).

EXAMPLE 34

4'-Butyl-α-phosphono[1,1'-biphenyl]-4-butanesulfonic acid, tripotassiumsalt

A. 4'-Butyl[1,1'-biphenyl]-4-propanoic acid, ethyl ester

To a stirred solution of 3.20 g (15.0 mmol) of 1-bromo-4-butylbenzene(Aldrich Chemical Company #33,576-2) at -78° C. under argon was added,dropwise over 30 min, 18.0 mL (30.6 mmol, 1.7M in pentane) oft-butyllithium solution. The resulting light yellow solution was warmedto 0° C. and stirred for 1 h. To this solution was added 3.4 g (25 mmol)of thrice-fused zinc chloride in 20 mL of THF. The resulting slurry wasstirred for 30 min and then a solution of 2.0 g (6.5 mmol) of4-iodobenzenepropanoic acid, ethyl ester (Example 43, Part B) and 0.4 g(0.35 mmol) of tetrakis(triphenylphosphine)-palladium(0) in 5 mL of THFwas added. The reaction was stirred for 16 h, diluted with ether andwashed once with 10% citric acid. The organic phase was dried (MgSO₄)and evaporated. Purification by flash chromatography on silica gel (5×20cm column) eluted with 1:1 hexanes/dichloromethane gave title compoundas a colorless oil, 1.79 g , 91% yield.

B. 4'-Butyl[1,1'-biphenyl]-4-propanol

To a stirred solution of 1.72 g (5.54 mmol) of Part A ester in 10 mL ofTHF at room temperature under argon was added, over the course of 2 min,a solution of 4 mL (4 mmol, 1M in THF) of lithium aluminum hydride. Theresulting solution was stirred for 16 h. The reaction was quenched with1M sodium potassium tartrate and extracted twice with ether. The etherextracts were dried over MgSO₄, filtered and evaporated.Recrystallization from hexanes provided title alcohol as a white solid,1.19 g, 80% yield, mp 62°-64° C.

C. 4'-Butyl[1,1-biphenyl]-4-propyl iodide

To a stirred solution of 1.19 g (4.43 mmol) of Part B alcohol, 1.16 g(4.43 mmol) of triphenylphosphine, and 0.66 g (7.4 mmol) of imidazole in15 mL of THF under argon at room temperature was added a solution of1.12 g (4.7 mmol) of iodine in 5 mL of THF, dropwise over 20 min. Afteraddition was complete, the reaction was diluted with hexanes and washedonce with saturated sodium bisulfite solution. The organic phase wasdried (MgSO₄) and evaporated. Purification by flash chromatography onsilica gel (5×20 cm column) eluted with dichloromethane gave titleiodide as a white waxy solid, 1.52 g, 91% yield.

D. 4'-Butyl-α-(diethoxyphosphinyl) [1,1'-biphenyl]-4-butanesulfonicacid, cyclohexyl ester

To a stirred slurry of 190 mg (4.75 mmol, 60% mineral oil dispersion) ofsodium hydride in 5 mL of DMF under argon at -10° C. was added asolution of 1.66 g (5.28 mmol) of Example 1A Part B sulfonate in 2 mL ofDMF. After addition was complete, the reaction was warmed to roomtemperature and stirred for 30 min. To the resulting solution was addeda solution of 1.00 g (2.64 mmol) of Part C iodide in 5 mL of DMF. Thereaction was stirred for 16 h, diluted with ether and washed once with10% citric acid and thrice with water. The organic phase was dried(MgSO₄) and evaporated. Purification by flash chromatography on silicagel (5×25 cm column) eluted with 3:47 ether/dichloromethane gave titlecompound as a colorless oil, 0.825 g, 55% yield.

E. 4'-Butyl-α-Phosphono[1,1'-biphenyl]-4-butanesulfonic acid,tripotassium salt

To a stirred solution of 0.82 g (1.55 mmol) of Part F ester in 5 mL ofdichloromethane under argon at room temperature was added 0.62 mL (4.7mmol) of bromotrimethylsilane. After 24 h, the resulting clear solutionwas evaporated at 25° C. and the residue dissolved in 10 mL of THF. Tothis stirred solution was added 0.8 g (5 mmol) of dried, finely groundpotassium iodide and 5 mg (0.015 mmol) of 18-crown-6. The resultingslurry was heated to reflux for 24 h, evaporated and then stirred for 1h with 5 mL (5 mmol) of 1.0M potassium hydroxide solution. The solutionwas lyophilized and then purified by MPLC (2.5×20 cm column of CHP-20Presin): 11.5 mL fractions, 6 mL/min flow rate, eluded with 250 mL ofwater, then a gradient of 450 mL of 3:1 acetonitrile/water into 450 mLof water). Fractions 32-40 were collected and lyophilized to give titlesalt as a white solid, 425 mg, 49% yield.

IR (KBr pellet) 3424, 3027, 2957, 2930, 2859, 1653, 1499, 1200, 1078,966 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ7.47 (d, 2H, J=8.1 Hz) 7.46 (d, 2H, J=8.1 Hz)7.27 (d, 2H, J=8.1 Hz) 7.21 (d, 2H, J=8.6 Hz) 2.79 (ddd, 1H, J=17.5,5.6, 3.8 Hz) 2.55 (m, 4H) 1.92 (m, 4H) 1.46 (m, 2H) 1.19 (m, 4H) 0.75(t, 3H, J=7.5 Hz) ppm.

Anal. Calc'd for C₂₀ H₂₄ K₃ O₆ PS.0.75 H₂ O: C, 43.34; H, 4.64; P, 5.59;S, 5.78 Found: C, 43.01; H, 4.88; P, 5.16; S, 6.21.

Mass Spec (FAB, + ions) m/e 579 (M+K), 541 (M+H), 503 (M-K+2H), 465(M-2K+3H).

EXAMPLE 35

(E)-6-Methyl-1-phosphono-9-(4-propylphenyl)-5-nonene-1-sulfonic acid,tripotassium salt

A. Bromo(4-propylphenyl)magnesium

A solution of 30.80 mL (0.20 mol) of 1-bromo-4-propylbenzene in 50 mLdry THF was added to 9.60 g (0.40 mol) of magnesium turnings in 200 mLTHF at a rate to maintain low reflux. After the addition was complete,the reaction was heated to 55° C. for one hour. The THF solution wastransferred via cannula to a sure-seal bottle and sealed for storage.Titration of 3.00 mL of the title Grignard reagent with 1N isopropanolin toluene against 2,2'-biquinoline as an indicator required volumes of5.4 and 5.3 mL, indicating the concentration to be 1.74N.

B. 2,2-Dimethylpropanoic acid, (E)-8-iodo-5-methyl-4-octen-1-yl ester

The above iodide is prepared as described in Example 35 Part A.

C. (E)-5-Methyl-8-(4-propylphenyl)-4-octen-1-ol

A solution of 2.15 g (6.10 mmol) of Part B iodide in 10 mL THF at 0° C.was treated with 10 mg (1 mol %) of copper iodide and 21.00 mL (36.60mmol) of the 1.74N solution of Part A Grignard reagent. The mixture wasstirred for one hour at 0° C. and fifteen hours at RT, at which time anadditional 7.00 mL (12.00 mmol) of Part A Grignard reagent were added.After twenty four hours, the reaction was chilled to 0° C. and quenchedwith 105 mL ammonium chloride and diluted with 200 mL ether and 1.00 mLammonium hydroxide. The aqueous fraction was removed and the organicswere washed with ammonium chloride solution (3×30 mL), water (2×30 mL),saturated sodium chloride (30 mL), dried (sodium sulfate), andconcentrated. The resulting oil was purified by flash chromatography onsilica gel packed, loaded, and eluted with 85:15 hexane/ethyl acetate.Pure fractions (#67-100) were combined and concentrated to yield 1.11 g(69%) of title alcohol as a clear oil.

TLC (7:3 hexane/ethyl acetate) R_(f) =0.18.

MS (CI, NH₃, + ions) m/e 261 (M+H), 278 (M+NH₄).

IR (neat) 3335, 2959, 2932, 2861, 1898, 1669, 1539, 1456, 1379, 1059,802 cm⁻¹.

¹ H NMR (CDCl₃, 400 MHz) δ7.11 (s, 4H) 5.19 (t, 1H, J=7.5 Hz) 3.66 (t,2H, J=6.4 Hz) 2.58 (m, 4H) 2.12 (q, 2H, J=7.5 Hz) 2.05 (t, 2H, J=7.5 Hz)1.76 (m, 2H) 1.64 (m, 4H) 1.63 (s, 3H) 0.97 (t, 3H, J=7.5 Hz) ppm.

D. (E)-1-(8-Iodo-4-methyl-4-octen-1-yl)-4-propylbenzene

A solution of 1.11 g (4.20 mmol) of Part C alcohol in 5 mL CH₂ Cl₂ at 0°C. was treated sequentially with 10 mg (2.5 mol %) of4-dimethylaminopyridine, 0.36 mL (5.50 mmol) of triethylamine, and 0.77mL (4.70 mmol) of methanesulfonyl chloride. The reaction was allowed tostir at room temperature for 80 minutes before diluting with ether. Theorganic solution was washed with water (2×25 mL), saturated sodiumchloride, dried (sodium sulfate), and evaporated to a clear oil. The oilwas dissolved in 20 mL acetone and stirred with 1.92 g (12.80 mmol) ofsodium iodide for fifteen hours. The reaction was driven to completionby heating at 50° C. for three more hours, then concentrated to aslurry, which was redissolved in hexane and water. The aqueous layer wasremoved, and the organic layer was washed with water, saturated sodiumsulfite, saturated sodium chloride, dried (sodium sulfate), andevaporated. The resulting yellow oil was purified by flashchromatography on silica gel (100 g), packed, loaded, and eluted withhexane. Pure fractions were combined and concentrated to yield 1.04 g(67%) of title iodide as a clear oil.

TLC (85:15 hexane/ethyl acetate): R_(f) =0.70.

MS (CI, NH₃, + ions) m/e 270 (M+H).

IR (film) 2957, 2930, 2859, 1514, 1456, 1445, 1379, 1341, 1316, 1227,1202, 1165, 1092, 1020, 839, 820, 802, 739 cm⁻¹.

¹ H NMR (CDCl₃, 400 MHz) δ7.24 (s, 4H) 5.24 (t, 1H, J=7.5 Hz) 3.33 (t,2H, J=7.0 Hz) 2.69 (q, 4H, J=6.0 Hz) 2.26 (q, 2H, J=7.2 Hz) 2.18 (t, 2H,J=7.5 Hz) 2.01 (quint, 2H, J=7.0 Hz) 1.86 (m, 2H) 1.78 (s, 3H) 1.77 (m,2H) 1.09 (t, 3H, J=7.2 Hz) ppm.

E.(E)-1-(Diethoxyphosphinyl)-6-methyl-9-(4-propylphenyl)-5-nonenesulfonicacid, cyclohexyl ester

To a solution of 1.53 g (4.87 mmol) of Example 1A Part B sulfonate in4.00 mL DMF at -20° C. was added 84.5 mg (3.25 mmol) of sodium hydride.The reaction was stirred at -20° C. until hydrogen evolution diminished,and at RT until gas evolution subsided completely, when 1.0 g (2.71mmol) of Part D iodide in 1.0 mL DMF was added. After stirring at RT for23 hours, the reaction was quenched with 5 mL ammonium chloride anddiluted with ether and water. The aqueous layer was removed and theorganic layer was washed with saturated sodium chloride. The combinedaqueous fractions were back extracted with ether, and the combinedorganic fractions were dried (sodium sulfate) and concentrated to an oil(1.84 g). The crude product was purified by flash chromatography onsilica gel (140 g), packed, loaded, and eluted with 70:30 hexane/ethylacetate. Pure fractions (#57-103) were combined and concentrated toyield 0.58 g (38%) of title compound as a clear oil.

TLC (7:3 hexane/ethyl acetate) R_(f) =0.18.l

MS (CI, NH₃, + ions) m/e 557 (M+H), 574 (M+NH₄).

IR (film) 2934, 2863, 1614, 1452, 1354, 1262, 1175, 1053, 1024, 972,930, 866, 828, 802, 758 cm⁻¹.

¹ H NMR (CDCl₃, 400 MHz) δ7.01 (s, 4H) 5.05 (t, 1H, J=6.6 Hz) 4.76 (m,1H) 4.15 (m, 4H) 3.35 (dt, 1H, J=19.6 Hz, 6.2 Hz) 2.46 (m, 4H) 2.04 (m,2H) 1.94 (m, 6H) 1.62 (m, 8H) 1.52 (s, 3H) 1.43 (m, 1H) 1.31 (m, 5H)1.27 (t, 6H, J=6.8 Hz) 0.86 (t, 3H, J=7.3 Hz) ppm.

F. (E)-6-Methyl-1-phosphono-9-(4-propylphenyl)-5-nonene-1-sulfonic acid,tripotassium salt

A solution of 0.57 g (1.02 mmol) of Part E compound in 10 mL methanol ina sealable tube was chilled to 0° C. and saturated with ammonia gas. Thetube was then sealed and heated at 65° C. for twenty four hours. Aftercooling, the tube was opened and the methanol evaporated. The residuewas dissolved in toluene and evaporated twice (2×10 mL), leaving aglassy oil. The oil was dissolved in 2.00 mL of methylene chloride andtreated sequentially with 1.38 mL (5.20 mmol) of bistrimethylsilyltrifluoroacetamide and 0.83 mL (6.24 mmol) of trimethylsilyl bromide.The reaction stirred for 24 hours, at which point the organics wereremoved under vacuum, and the residue treated with 6.00 mL (6.00 mmol)of 1N KOH and lyophilized. The crude product was purified by MPLC on acolumn of CHP-20P gel (2.5 cm diam.×25 cm height) eluting with water(100 mL) followed by a gradient created by the gradual addition of 400mL acetonitrile to a resevoir of 350 mL water. Approximately 7 mLfractions were collected. Pure fractions (#41-45) were combined andconcentrated to yield 348 mg (64%) of a waxy solid, which was trituratedwith acetone (3×2.00 mL) and dried on high vacuum to yield 270 mg (50%)of title compound, as an off-white solid.

TLC (5:4:1 n-propanol/ammonium hydroxide/water) R_(f) =0.22.

MS (FAB, + ions) 533 (M+H), 457 (M+H-K).

IR (KBr) 3235, 2934, 2872, 1653, 1458, 1144, 1098, 1052, 964 cm⁻¹.

¹ H NMR (CDCl₃, 400 MHz) δ7.07 (s, 4H) 5.16 (m, 1H) 2.76 (m, 1H) 2.42(m, 4H) 1.79 (m, 6H) 1.53 (m, 2H) 1.48 (s, 3H) 1.43 (m, 2H), 0.74 (t,2H, J=7.3 Hz) ppm.

Anal. Calc'd for C₁₉ H₂₈ O₆ PSK₃ -H₂ O: C, 41.43; H, 5.49; S, 5.82; P,5.62; Found C, 41.43; H, 5.72; S, 6.23; P, 5.29.

EXAMPLE 35A

2,2-Dimethylpropanoic acid, (E) -8-iodo-5-methyl-4-octen-1-yl-ester

(1). 2,2-Dimethylpropanoic acid, (E) -5,9-dimethyl-4,8-decadienyl ester

To a solution of 10.00 g (54.94 mmol) of Example 2 Part D alcohol in 50mL of dichloromethane at 0° C. was added 0.67 g (5.50 mmol) of4-dimethylaminopyridine (DMAP) and 11.49 mL (82.41 mmol) oftriethylamine followed by the addition of 8.12 mL (65.93 mmol) oftrimethylacetyl chloride over 15 min. The reaction mixture was stirredfor 1 h at 0° C. and 2.5 h at room temperature. The suspension wasdiluted with 200 mL of dichloromethane and 300 mL of water. The layerswere separated and the organic fraction was washed with solutions ofKHSO₄, NaHCO₃ and NaCl, dried (MgSO₄) and concentrated to provide titlecompound as a colorless liquid.

TLC Silica gel (8:2 hexanes/ethyl acetate) R_(f) =0.25.

(2). 2,2-Dimethylpropanoic acid, (E)-8-bromo-9-hydroxy-5,9-dimethyl-4-decenyl ester

To a solution of 10.00 g (37.59 mmol) of Part (1) ester in 100 mL of asolution of 7:3 t-butanol/water at 0° C. was added 6.69 g (37.59 mml) ofN-bromosuccinimide portionwise with the aid of a solid addition funnelover 0.5 h. The reaction mixture was stirred at 0° C. for 3 h, dilutedwith 300 mL of ether, washed with solutions of K₂ CO₃ and NaCl, dried(MgSO₄) and concentrated. The residue obtained was purified by flashchromatography (800 g of silica gel) eluting with 9:1 hexanes/ethylacetate to provide 11.30 g (63%) of title alcohol as a colorless oil.

TLC Silica gel (8:2 hexanes/ethyl acetate) R_(f) =0.42.

(3). 2,2-Dimethylpropanoic acid, (E)-8,9-epoxy-5,9-dimethyl-4-decenylester

To a stirred solution of 11.00 g (30.30 g) of Part (2) alcohol in 100 mLof THF at -78° C. was added 21.68 mL (30.30 mmol) of a 1.4M potassiumbis(trimethylsilyl)amide solution in THF over 15 min. The reactionmixture was stirred at -78° C. for 0.5 h and then warmed to roomtemperature over 2 h. The mixture was quenched with 200 mL of water anddiluted with 150 mL of dichloromethane. The layers were separated andthe organic fraction washed with water, dried (MgSO₄) and concentratedto provide 8.57 g (100%) of title epoxide as a pale yellow oil.

TLC Silica gel (9:1 hexanes/ethyl acetate) R_(f) =0.38.

(4). 2,2-Dimethylpropanoic acid, (E)-5-methyl-8-oxo-4-octenyl ester

To a stirred solution of 8.50 g (30.14 mmol) of Part (3) epoxide in 100mL of THF at 0° C. was added 6.90 g (30.27 mmol) of periodic acid over15 min. The reaction mixture was stirred at 0° C. for 1 h, when it wasdiluted with 200 mL of ether and 200 mL of water. The layers wereseparated and the organic fraction was washed with solutions of NaHCO₃and brine, dried (MgSO₄), and concentrated. The residue (≈7.5 g)obtained was purified by flash chromatography (800 g of silica gel)eluting with 95:5 hexanes/ethyl acetate to provide 4.25 g (59%) of titlealdehyde as an oil.

TLC Silica gel (9:1 hexanes/ethyl acetate) R_(f) =0.28.

(5). 2,2-Dimethylpropanoic acid, (E)-5-methyl-8-hydroxy-4-octenyl ester

To a stirred solution of 2.00 g (8.33 mmol) of Part (4) aldehyde in 20mL of methanol at 0° C. was added 0.16 g (4.17 mmol) of NaBH₄. Thereaction mixture was stirred for 0.5 h, when it was diluted with etherand quenched with NH₄ Cl solution. The layers were separated and theorganic fraction was washed with solutions of NaHCO₃ and brine, dried(MgSO₄) and concentrated to provide 2.00 g (100%) of title alcohol as acolorless oil.

TLC Silica gel (9:1 hexanes/ethyl acetate) R_(f) =0.06.

(6). 2,2-Dimethylpropanoic acid,(E)-5-methyl-8-[(methylsulfonyl)oxy]-4-octenyl ester.

A solution of 2.00 g (8.26 mmol) of Part (5) alcohol in 20 mL ofmethylene chloride and 1.50 mL (10.74 mmol) of triethylamine at 0° C.was treated with 0.77 mL (9.91 mmol) of methanesulfonyl chloridedropwise over 0.2 h. The reaction mixture was stirred for 2.0 h when itwas quenched with saturated aqueous KHSO₄ solution and diluted withether. The layers were separated and the organic fraction was washedwith solutions of NaHCO₃ and brine, dried (Na₂ SO₄) and evaporated toprovide title mesylate as a pale yellow oil.

(7). 2,2-Dimethylpropanoic acid, (E)-8-iodo-5-methyl-4-octenyl ester

The crude Part (6) mesylate (≈8.0 mmol) was diluted with 100 mL ofacetone and treated with 5.86 g (39.06 mmol) of NaI at room temperaturefor 48 h. The mixture was diluted with 200 mL of hexane and extractedwith NaHSO₃, brine, dried (MgSO₄) and concentrated to provide acolorless oil. The oil was purified by flash chromatography (80 g ofsilica gel) eluting with 8:2 ethyl acetate/hexane to provide 2.11 g(77%) of title iodide as a colorless oil.

TLC Silica gel (8:2 hexane/ethyl acetate) R_(f) =0.81.

EXAMPLE 36

(E)-6-Methyl-8-phenyl-1-phosphono-5-octene-1-sulfonic acid, tripotassiumsalt

A. 4-[(t-Butyldimethylsilyl)oxy]-1-butanol

To a solution of 300 mL of THF, 90 g (1 mol) of butanediol and 13.6 g(0.20 mol) of imidazole was added 30.1 g (0.20 mol) oft-butyldimethylsilyl chloride in 50 mL of THF. After 2 h the reactionmixture was diluted with 700 mL of water and 500 mL of diethyl ether.The layers were equilibrated and separated. The organic fraction waswashed with water, dried (MgSO₄) and concentrated to leave 38.7 g (95%)of title alcohol as a colorless oil.

TLC Silica gel (3:7 ehtyl acetate/hexane) R_(f) =0.35.

IR (neat) 3450, 2940, 2880, 1465, 1385, 1250, 1100, 1055, 835, 770 cm⁻¹.

¹ H NMR (CDCl₃, 300 MHz) δ3.59 (t, 2H, J=5.7 Hz) 3.56 (t, 2H, J=5.9 Hz)3.40 (m, 1H, OH) 1.58 (m, 4H) 0.83 (s, 9H) 0.00 (s, 6H) ppm.

Mass Spec (CI--NH₃, + ions) m/e 205 (M+H).

B. 4-[(t-Butyldimethysilyl)oxy]butanol

To a solution of 100 mL of methylene chloride and 3.21 g (41.17 mmol) ofmethyl sulfoxide at -78° C. was added 6.67 g (37.74 mmol) of oxalylchloride dropwise over 15 min. After gas evolution ceased (≈15 min.),7.0 g (34.31 mmol) of Part A alcohol was added to the reaction mixture.The mixture was stirred at -78° C. for 0.5 h, when 13.8 g (137.2 mmol)of triethylamine was added rapidly over 4 min. The mixture was warmed to-20° C. over 0.5 h and quenched with 200 mL of ether and 200 mL ofwater. The layers were equilibrated and separated. The organic fractionwas dried (Na₂ SO₄) and concentrated to leave 5.85 g (85%) of titlealdehyde as a colorless oil.

TLC Silica gel (1:9 ethyl acetate/hexane) R_(f) =0.45.

¹ H NMR (CDCl₃, 300 MHz) δ9.75 (t, 1H, J=2.5 Hz) 3.60 (t, 2H, J=5.0 Hz)2.45 (td, 2H, J=2.5, 5.5 Hz) 1.83 (quint., 2H, J=6.5 Hz) 0.90 (s, 9H)0.03 (s, 6H) ppm.

C. (E)-2-Methyl-6-[(t-butyldimethylsilyl) oxy]-2-hexenoic acid, ethylester

To a solution of 8.62 g (36.25 mmol) of triethyl 2-phosphonopropionatein 50 mL of THF at 0° C. was added 0.84 g (35.0 mmol) of NaH in threeequal portions over 15 min. After gas evolution ceased, 5.85 g (29 mmol)of Part B aldehyde was added in one portion. The mixture was warmed toRT over 30 min. and diluted with 100 NH₄ Cl solution and 100 mL ofether. The layers were equilibrated and separated. The organic fractionwas dried (Na₂ SO₄) and concentrated. The remainder was purified byflash chromatography (300 g of silica gel ) with 5:95 ethylacetate/hexanes to yield 5.50 g (66%) of title ester as an amber oil.

TLC Silica gel (1:9 ethyl acetate/hexanes) R_(f) =0.33.

¹ H NMR (CDCl₃, 300 MHz) δ6.72 (t, 1H, J=7.0 Hz) 4.15 (q, 2H, J=7.2 Hz)3.59 (t, 2H, J=6.1 Hz) 2.20 (q, 2H, J=7.8 Hz) 1.77 (s, 3H) 1.60 (quint.,2H, J=7.0 Hz) 1.23 (t, 3H, J=7.0 Hz) 0.90 (s, 9H) 0.05 (s, 6H) ppm.

D. (E)-2-Methyl-6-[(t-butyldimethylsilyl) oxy]-2-hexen-1-ol

To a solution of 25 mL of dichloromethane and 5.20 g (18.18 mmol) ofPart C ester at -78° C. was added 40 mL (40 mmol) of a 1M solution ofdiisobutylaluminum hydride in cyclohexane over 20, min. After 1 h, themixture was diluted with 100 mL (100 mmol) of an aqueous 1M solution ofsodium potassium tartrate and 100 mL of ether. The mixture was stirredat RT for 2.5 h when the layers were separated, the organics dried (Na₂SO₄) and concentrated. The remainder was purified by flashchromatography (250 g silica gel ) with 15:85 ethyl acetate/hexanes toyield 3.0 g (67%) of title alcohol as a colorless oil.

TLC Silica gel (3:7 ethyl acetate/hexanes) R_(f) =0.45.

IR (film) 3347, 2953, 2859, 1472, 1406, 1256, 1098, 837 cm⁻¹.

¹ H NMR (CDCl₃, 300 MHz) δ5.38 (t, 1H, J=7.2 Hz) 3.93 (d, 2H, J=4.2 Hz)3.56 (t, 2H, J=6.4 Hz) 2.04 (q, 2H, J=7.4 Hz) 1.94 (t, 1H, J=4.0 Hz, OH)1.61 (s, 3H) 1.53 (quint., 2H, J=6.6 Hz) 0.87 (s, 9H) 0.00 (s, 6H)ppm.

Mass Spec (CI--NH₃, + ions) m/e 262 (M+NH₄), 245 (M+H), 227 (M+H-H₂ O).

E. (E)-1-Chloro-2-methyl-6-[(E-butyldimethylsilyl)oxy]-2-hexene

To a solution of 30 mL of dichloromethane, 3.00 g (13.30 mmol) of Part Dalcohol and 2.83 g (28.00 mmol) of triethylamine at 0° C. was added 1.60g (14.00 mmol) Of methanesulfonyl chloride in 5 mL of dichloromethane.After 2 h the reaction mixture was diluted with 70 mL of water and 125mL of diethyl ether. The layers were equilibrated and separated. Theorganic fraction was washed with water, dried (Na₂ SO₄) and concentratedto leave the crude mesylate. The residue was diluted with 10 mL ofdimethylformamide and treated with 1.70 g (40.00 mmol) of LiCl. Thereaction mixture was stirred at RT for 6 h, at which point it wasdiluted with 100 mL of ether and 100 mL of water. The layers wereequilibrated and the organic fraction dried (Na₂ SO₄) and concentrated.The residue was purified by flash chromatography (100 g of silica gel)with 2:98 ethyl acetate/hexane to yield 1.20 g (35%) of title chlorideas an amber oil.

TLC Silica gel (1:9 ethyl acetate/hexane) R_(f) =0.80.

IR (film) 2930, 2859, 1472, 1389, 1256, 1103, 837 cm⁻¹.

¹ H NMR (CDCl₃, 400 MHz) δ5.50 (t, 1H, J=7.0 Hz) 3.95 (s, 2H) 3.57 (t,2H, J=6.5 Hz) 2.04 (q, 2H, J=7.5 Hz) 1.70 (s, 3H) 1.65 (quint., 2H,J=6.6 Hz) 0.87 (s, 9H) 0.00 (s, 6H) ppm.

Mass Spec (CI--NH₃, + ions) m/e 263, 265 (M+H), 227 (M+H-HCl).

F. (E)-3-Methyl-1-phenyl-7-[(t-butyldimethylsilyl) oxy]-3-heptene

A solution of 3 mL (6 mmol) of 2M benzylmagnesium chloride in THF and 2mL of HMPA at 0° C. was treated dropwise with 1.0 g (3.80 mmol) of PartE chloride in 5 mL of THF over 5 min. The solution was allowed to warmto RT and stir for 2 h, at which point the reaction was diluted withether and 3 mL (3 mmol) of 1N HCl solution. The organic layer was washedtwo times with NH₄ Cl solution, dried (MgSO₄) and concentrated to anoil. The oil was purified by flash chromatography performed on 125 g ofsilica gel packed, loaded and eluted with 3:95 ethyl acetate/hexane toprovide 1.10 g (91%) of title compound as a colorless oil.

TLC Silica gel (5:95 ethyl acetate/hexane) R_(f) =0.80.

IR (film) 3086, 3063, 3028, 2930, 2859, 1603, 1497, 1472, 1256, 1101,1032, 1007, 964, 837 cm⁻¹.

¹ H NMR (CDCl₃, 300 MHz) δ7.20, 7.10 (two m, 5H) 5.10 (t, 1H, J=7.0 Hz)3.56 (t, 2H, J=6.4 Hz) 2.65 (t, 2H, J=7.5 Hz) 2.23 (t, 2H, J=7.4 Hz)1.97 (q, 2H, J=6.8 Hz) 1.60 (s, 3H) 1.48 (quint., 2H, J=7.0 Hz) 0.87 (s,9H) 0.00 (s, 6H) ppm.

Mass Spec (CI--NH₃, + ions) m/e 336 (M+NH₄), 319 (M+H).

G. (E)-5-Methyl-7-phenyl-4-hepten-1-ol

A solution of 2 mL of THF and 1.10 g (3.45 mmol) of Part F compound at0° C. was treated dropwise with 0.30 mL (5.00 mmol) of acetic acid and4.0 mL (4.00 mmol) of a 1M tetrabutylammonium fluoride solution in THF.The solution was allowed to warm to RT and stir for 48 h, at which pointthe reaction was diluted with 50 mL of ether and 25 mL of NaHCO₃solution. The organic layer was washed two times with NaHCO₃ solution,dried (MgSO₄) and concentrated to an oil. Flash chromatography wasperformed on 80 g of silica gel packed, loaded and eluted with 3:7 ethylacetate/hexane to provide 0.59 g (83%) of title alcohol as a colorlessoil.

TLC Silica gel (3:7 ethyl acetate/hexane) R_(f) =0.60.

IR (film) 3339, 3027, 2932, 2859, 1603, 1452, 1385, 1231, 1181, 1057,698 cm⁻¹.

¹ H NMR (CDCl₃, 400 MHz) δ7.25, 7.15 (two m, 5H) 5.13 (t, 1H, J=6.8 Hz)3.54 (t, 2H, J=6.4 Hz) 2.70 (t, 2H, J=7.7 Hz) 2.23 (t, 2H, J=7.7 Hz)2.04 (q, 2H, J=7.3 Hz) 1.70 (s, 1H, OH) 1.65 (s, 3H) 1.55 (quint, 2H,J=7.7 Hz) ppm.

Mass Spec (CI--NH₃, + ions) m/e 222 (M+NH₄), 205 (M+H).

H. (E)-1-Iodo-5-methyl-7-phenyl-4-heptene

To a stirred solution of 0.59 g (2.89 mmol) of Part G alcohol and 0.66mL (6.00 mmol) of triethylamine in 10 mL of methylene chloride at 0° C.was added 0.37 g (3.20 mmol) of methanesulfonyl chloride dropwise over10 min. After 1 h at 0° C. the reaction was diluted with ether andwashed with aqueous solutions of NH₄ Cl, NaHCO₃, and brine. The organicswere dried (Na₂ SO₄) and concentrated under reduced pressure to providethe crude mesylate. The residual oil was dissolved in 25 mL of acetoneand treated with 1.00 g (6.66 mmol) of NaI. The resulting solution wasstirred at RT for 36 h and diluted with ether. The organics were washedwith water, dried over MgSO₄, and concentrated to provide a yellow oil.Flash chromatography was performed on 100 g of silica gel packed, loadedand eluted with hexanes to provide 0.68 g (2.16 mmol, 100% overallyield) of title iodide as a colorless oil.

TLC Silica gel (hexane) R_(f) =0.27.

IR (film) 3061, 3027, 2932, 2857, 1603, 1495, 1452, 1204, 1165, 1030,743, 698 cm⁻¹.

¹ H NMR (CDCl₃, 400 MHz) δ7.25, 7.15 (two m, 5H) 5.03 (t, 1H, J=7.3 Hz)3.05 (t, 2H, J=7.3 Hz) 2.70 (t, 2H, J=7.7 Hz) 2.28 (t, 2H, J=7.7 Hz)2.06 (q, 2H, J=7.3 Hz) 1.80 (quint, 2H, J=7.3 Hz) 1.67 (s, 3H) ppm.

Mass Spec (CI--NH₃, + ions) m/e 332 (M+NH₄), 314 (M).

I. (E)-1-(Diethoxyphosphinyl)-6-methyl-8-phenyl-5-octenesulfonic acid,cyclohexyl ester

To a suspension of 83 mg (3.44 mmol) of NaH in 7 mL of dry DMF at 0° C.under argon was added 1.25 g (4.00 mmol) of Example 1A Part B sulfonateover 15 min. to give a yellow solution. The reaction was allowed to warmto room temperature and stir for 0.5 h when 0.60 g (1.91 mmol) of Part Hiodide was added in one portion. The reaction mixture was stirred for 18h when it was quenched with saturated aq NH₄ Cl solution and dilutedwith ether. The organic fraction was washed with water, brine, dried(Na₂ SO₄) and evaporated to provide a crude yellow oil. Flashchromatography was performed on 75 g of silica gel eluted with 4:6 ethylacetate/hexane to provide 0.76 g (79%) of title compound as a paleyellow oil.

TLC Silica gel (3:7 ethyl acetate/hexane) R_(f) =0.28.

IR (film) 3059, 3026, 2938, 2863, 1454, 1354, 1261, 1172, 1053, 1022,927, 866 cm⁻¹.

¹ H NMR (CDCl₃, 270 MHz) δ7.25, 7.15 (two m, 5H) 5.13 (t, 1H, J=7.3 Hz)4.86 (m, 1H) 4.22 (m, 4H) 3.45 (dt, 1H, J=20.1, 6.5 Hz) 2.70 (t, 2H,J=7.3 Hz) 2.26 (t, 2H, J=7.8 Hz) 2.05 (m, 6H) 1.67 (m, 6H) 1.62 (s, 3H)1.36 (t+m, 10H, J=7.0 Hz) ppm.

Mass Spec (CI--NH₃, + ions) m/e 518 (M+NH₄), 436 (M+NH₄ -C₆ H₁₀).

J. (E)-6-Methyl-8-phenyl-1-phosphono-5-octene-1-sulfonic acid,tripotassium salt

To a solution of 0.76 g (1.52 mmol) of Part I compound and 10 mL ofmethanol in a sealable tube at 0° C. was added NH₃ (g) until thesolution was saturated. The tube was sealed and placed in an oil bath at60° C. for 24 h, at which point the tube was opened and the volatilesremoved under reduced pressure. The remainder was dissolved in a 1:3hexamethyldisiiazane/toluene solution and evaporated two times (2×10 mL)leaving a colorless viscous oil. The oil was dissolved in 7 mL of drymethylene chloride and treated with 1.48 mL (7.00 mmol) ofhexamethyldisilazane and 1.00 mL (7.50 mmol) of bromotrimethylsilane.The reaction was allowed to stir at RT for 18 h when the solvent wasevaporated and the residue pumped (≈0.5 mm pressure) for 0.5 h. Theremainder was dissolved by adding 5 mL (5 mmol) of 1M KOH solution andstirring vigorously for ten min. The soapy solution was freeze dried toprovide a white solid. The solid was purified by MPLC on a column ofCHP20P gel (250 mL ) eluting with water (150 mL) followed by a gradientcreated by the gradual addition of 500 mL of acetonitrile to a reservoirof 300 mL of water. Approximately 7 mL fractions were collected.Fractions 26 to 30 were pooled, the acetonitrile was removed underreduced pressure and the aqueous solution lyophilized to provide 0.45 g(63%) of title compound as a white lyophilate which was 98.5% pure byHPLC.

TLC Silica gel (6:3:1 n-propanol/conc. NH₃ /water) R_(f) =0.17.

IR (KBr) 3418, 3063, 3027, 2934, 2863, 1663, 1454, 1383, 1196, 1111,1086, 1047, 964, 698 cm⁻¹.

¹ H NMR (CDCl₃, 400 MHz) δ7.25, 7.15 (two m, 5H) 5.15 (t, 1H, J=7.4 Hz)2.77 (ddd, 1H, J=17.9, 7.5, 4.5 Hz) 2.64 (t, 2H, J=7.8 Hz) 2.20 (t, 2H,J=7.6 Hz) 1.97-1.65 (m, 4H) 1.57 (s, 3H) 1.46 (m, 2H) ppm.

Mass Spec (FAB, + ions) m/e 515 (M+K), 477 (M+H), 439 (M-K+2H).

Anal. Calc'd for C₁₅ H₂₀ O₆ SPK₃ +1.36 H₂ O: C, 35.95; H, 4.57; P, 6.18;S, 6.40 Found: C, 36.26; H, 4.76; P, 5.84; S, 6.21.

EXAMPLE 37

(E,E)-7,11,15-Trimethyl-1-phosphono-6,10,14-hexadecatriene-1-sulfonicacid, tripotassium salt

A. (E,E)-6,10,14-Trimethyl-5,9,13-pentadecatrienenitrile

A solution of 4.78 g (13.30 mmol) of(E,E)-4-iodo-2,6,10-trimethyl-2,6,10-tetradecatriene (prepared inExample 1 Part C) and 2.59 g (39.80 mmol) potassium cyanide in an 8:1mixture of ethanol/water was stirred at reflux overnight. The ethanolwas removed under vacuum and the reaction was diluted with 200 mL etherand 50 mL water. The aqueous fraction was removed and the organicswashed with water and brine. The combined aqueous fractions were backextracted with ether and the combined organics dried on sodium sulfateand concentrated to yield 3.00 g (87%) of title nitrile as a yellow oil.The compound was used without further purification.

TLC (Silica gel, 95:5 hexane/ethyl acetate) R_(f) =0.13.

MS (CI--NH₃ + ions) m/z 260 (M+H), 277 (M+NH₄).

IR (KBr) 2965, 2924, 2857, 2247, 1669, 1449, 1383, 1107, 833 cm⁻¹.

¹ H NMR (CDCl₃, 400 MHz) δ5.07 (m, 3H) 2.31 (t, 2H, J=7.5 Hz) 2.15 (q,2H, J=7.5 Hz) 2.03 (m, 8H) 1.71 (quint, 2H, J=7.5 Hz) 1.67 (s, 3H) 1.63(s, 3H) 1.60 (s, 6H) ppm.

B. (E,E)-6,10,14-Trimethyl-5,9,13-pentadecatrienal

To a stirred solution of 1.50 g (5.79 mmol) of Part A nitrile in 6.0 mLtetrahrydrofuran at 0° C. was added dropwise 5.80 mL (8.69 mmol) of 1.5Ndiisobutylaluminum hydride in toluene. After the addition was complete,the reaction was warmed to 50° C. in an oil bath for one hour. Thereaction was quenched at 0° C. with 6.0 mL water, and diluted with 26 mL1M tartaric acid and 15 mL ether. The mixture stirred at roomtemperature for 21/2 hours, and was extracted with ether two times. Thecombined organics were washed with brine, dried over sodium sulfate, andconcentrated to provide 1.50 g of title aldehyde as a yellow slurrywhich was used without further purification.

TLC (Silica gel, CH₂ Cl₂) R_(f) =0.55.

¹ H NMR (CDCl₃, 400 MHz) δ9.75 (s, 1H) 5.09 (m, 3H) 2.41 (dt, 2H, J=1.5,7.3 Hz) 2.10-1.93 (m, 10H) 1.68 (s+m, 5H) 1.59 (s, 9H) ppm.

C. (E,E)-6,10,14-Trimethyl-5,9,13-pentadecantrien-1-ol

To stirred solution of 1.50 g (5.77 mmol) of Part B aldehyde in 15 mLmethanol at 0° C. was added 330 mg (8.69 mmol) of sodium borohydride.After 15 minutes, the reaction was quenched with 5 mL ammonium chloridesolution and partitioned between 100 mL ether and 50 mL ammoniumchloride. The aqueous layer was removed and the organics were washedwith brine, dried (sodium sulfate), and concentrated to 1.3 g of ayellow oil. The product was purified by flash chromatography on silicagel (150 g) packed, loaded, and eluted with 7:3 hexane/ethyl acetate.Pure fractions were concentrated to yield 0.80 g (45%) of title alcoholas a clear oil.

TLC (Silica gel 7:3 hexane/ethyl acetate) R_(f) =0.32.

MS (CI--NH₃, + ions) 265 (M+H), 282 (M+NH₄).

IR (CH₂ Cl₂ film) 3331, 2928, 2859, 1451, 1383, 1061 cm⁻¹.

¹ H NMR (CDCl₃, 400 MHz) δ5.10 (m, 3H) 3.63 (t, 2H, J=6.5 Hz) 2.08 (m,4H) 2.00 (m, 6H) 1.68 (s, 3H) 1.59 (s, 9H) 1.55 (m, 2H) 1.40 (quint, 2H,J=6.5 Hz) ppm.

D. (E,E)-1-Iodo-6,10,14-trimethyl-5,9,13-pentadecatriene

To stirred solution of 0.78 g (2.95 mmol) of Part C alcohol in 10 mLmethylene chloride at 0° C. was added 18 mg (5 mol %) of 4-dimethylaminopyridine and 0.53 mL (3.83 mmol) of triethylamine followed by thedropwise addition of 0.35 mL (4.44 mmol) of methanesulfonyl chloridedissolved in 2.5 mL methylene chloride. The mixture was stirred at roomtemperature for 2 hours, when it was diluted with 100 mL ether and 25 mLwater. The aqueous fraction was removed and the organics were washedwith water and brine and dried (sodium sulfate). The product wasconcentrated to a yellow oil which was treated with 1.33 g (8.83 mmol)sodium iodide in 20 mL acetone at room temperature 16 hours and at 65°C. for two hours. The acetone was removed under vacuum and the orangeresidue dissolved in 80 mL hexane and 40 mL water. The aqueous layer wasremoved and the organics were washed with water, sodium sulfite (2×20mL), brine, and concentrated to 0.75 g of a yellow oil. The crudeproduct was purified by flash chromatography on silica gel (100 g)packed, loaded, and eluted with hexane. Pure fractions were combined andconcentrated to yield 610 mg (55%) of title iodide as a clear oil.

TLC Silica gel, (hexane) R_(f) =0.16.

MS (CI--NH₃, + ions) 375 (M+H), 392 (M+NH₄).

IR (CH₂ Cl₂ film) 2967, 2922, 2855, 1667, 1447, 1381, 1225, 1107 cm⁻¹.

¹ H NMR (CDCl₃, 400 MHz) δ5.02 (m, 3H) 3.10 (t, 2H, J=7.0 Hz) 2.00 (m,4H) 1.93 (m, 6H) 1.75 (quint, 2H, J=7.5 Hz) 1.60 (s, 3H) 1.52 (s, 9H)1.37 (quint, 2H, J=7.5 Hz) ppm.

E. (E,E) -1-(Diethoxyphosphinyl)-7,11,15-trimethyl-6,10,14-hexadecatrienesulfonic acid, cyclohexyl ester

To a stirred solution of 1.00 g (3.19 mmol) of Example 1A Part Bsulfonate in 4.0 mL dimethylformamide at -20° C. was added 69 mg (2.88mmol) of sodium hydride in one portion. The reaction was stirred at -20°C. for 20 minutes then at room temperature until gas evolution wascompleted (25 minutes), when 0.60 g (1.59 mmol) of Part D iodide in 2.0mL dimethylformamide was added. The mixture was stirred for 20 hours,when it was quenched with 25 mL ammonium chloride and diluted with 75 mLether. The aqueous fraction was removed, and the organics were washedwith brine. The combined aqueous fractions were back extracted withether and the combined organics were dried (sodium sulfate) andconcentrated to 1.2 g of a yellow oil. The crude product was purified byflash chromatography on silica gel (100 g) packed, loaded, and eludedwith 7:3 hexane/ethyl acetate. Pure fractions were combined andconcentrated to yield 403 mg (45%) of title compound as a clear oil.

TLC (Silica gel 7:3 hexane/ethyl acetate) R_(f) =0.19.

¹ H NMR (CDCl₃, 400 MHz) δ5.10 (m, 3H) 4.85 (m, 1H) 4.23 (m, 4H) 3.42(dt, 1H, J=21, 6 Hz) 2.18-1.97 (m, 14H) 1.79-1.47 (m, 8H) 1.68 (s, 3H)1.59 (s, 9H) 1.40-1.25 (m, 2H) 1.36 (t, 6H, J=7.5 Hz) ppm.

F. (E,E)-7,11,15-Trimethyl-1-phosphono-6,10,14-hexadecatriene-1-sulfonicacid, tripotassium salt

A solution of 403 mg (0.72 mmol) of Part E triester in 10 mL of methanolin a sealable tube was saturated with ammonia gas at 0° C. The tube wassealed and heated at 75° C. for 20 hours. The tube was opened and thesolution evaporated to a glassy oil which was evaporated from toluenetwo times. The residue was treated with a solution of 16:5 mLtoluene/hexamethyldisilazane (HMDS) and evaporated (2×6.6 mL) beforedrying under high vacuum. The residue was dissolved in 4.5 mL ofmethylene chloride and treated sequentially with 0.76 mL (3.59 mmol) ofHMDS and 0.57 mL (4.31 mmol) of trimethylsilyl bromide. The reaction wasstirred at room temperature under argon for 48 hours, at which point theorganics were removed under vacuum and the remainder was dissolved in3.10 mL (3.1 mmol) of 1N KOH and lyophilized. The solid was purified byMPLC on a column of CHP20P gel (2.5 cm diameter×21 cm height), elutingwith water (100 mL), followed by a gradient formed by the gradualaddition of 400 mL acetonitrile to a reservoir of 350 mL water.Approximately 10 mL fractions were collected. Pure fractions werecombined and concentrated to 316 mg (81%) of a glassy solid. The solidwas triturated with acetone (3×2.0 mL) until a granular consistency wasachieved, and dried under vacuum, yielding 263 mg (68%) of titlecompound as an off-white solid.

TLC (Silica gel, 7:2:1 n-propanol/ammonia/water) R_(f) =0.10.

MS (Ion Spray, - ions) 421 (M-3K+2H).

IR (KBr) 3457, 2965, 2926, 2857, 16559, 1624, 1451, 1400, 1383, 1213,1173, 1140, 1090, 1044, 966, 885, 837, 785, 694, 644, 556 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ5.14 (t, 1H, J=6.6 Hz) 5.05 (m, 2H) 2.80 (dt,1H,J=18, 6 Hz) 1.97 (m, 4H) 1.88 (m, 6H) 1.78 (m, 2H) 1.55 (s, 3H) 1.49(s, 9H) 1.35-1.55 (m, 2H) 1.23 (m, 2H) ppm.

Anal. Calc'd for C₁₉ H₃₂ O₆ SPK₃ -1.21H₂ O: C, 40.85; H, 6.21; P, 5.54;S, 5.74. Found: C, 40.85; H, 6.32; P, 5.75; S, 5.60.

EXAMPLE 38

(all-E)-7,11,15-Trimethyl-1-phosphono-4-(3,7,11-trimethyl-2,6,10-dodecatrienyl)-6,10,14-hexadecatriene-1-sulfonicacid, tripotassium salt

A. (all-E)-Bis(3,7,11-trimethyl-2,6,10-dodecatrienyl)propanedioic acid,diethyl ester

To a stirred solution of 6.57 g (41.10 mmol) of diethyl malonate in 80mL dimethylformamide (DMF) at -25° C. under argon was added 2.17 g(90.30 mmol) of sodium hydride. The reaction was stirred for 30 minutesat -25° C. and room temperature for 30 minutes when a solution of 23.42g (82.10 mmol) of farnesyl bromide in 20 mL of DMF was added. Thereaction mixture was stirred for 15 hours, quenched with 100 mL ammoniumchloride solution and diluted with 500 mL of a 1:1 hexane/ether mixture.The aqueous fraction was removed and the organics washed with brine,dried (sodium sulfate), and concentrated to yield 21.07 g of titlecompound as a yellow oil which was used without further purification.

TLC (Silica gel, 9:1 hexane/ethyl acetate) R_(f) =0.59.

¹ H NMR (400 MHz, CDCl₃) δ5.08 (t, 4H, J=6.2 Hz) 4.98 (t, 2H, J=7.5 Hz)4.16 (m, 4H) 2.60 (d, 4H, J=7.0 Hz) 2.01 (m, 20H) 1.68 (s, 6H) 1.60(s+m, 19H) 1.23 (m, 6H) ppm.

B.(all-E)-5,9,13-Trimethyl-2-(3,7,11-trimethyl-2,6,10-dodecatrienyl)-4,8,12-tetradecatrienoicacid, ethyl ester

A solution of 21.07 g (37.00 mmol) of Part A compound, 0.66 mL (37.00mmol) of water, and 3.14 g (74.10 mmol) of lithium chloride in 40 mL ofmethylsulfoxide was heated to 190° C. and stirred for 72 hours underargon. The reaction was treated with a 1:1 solution of hexane/ether andwashed with water and brine. The organic fraction was dried (sodiumsulfate), and concentrated to yield 18.00 g of title ester as a brownoil. The compound was used without further purification.

TLC (Silica gel, 9:1 hexane/ethyl acetate) R_(f) =0.73.

C.(all-E)-5,9,13-Trimethyl-2-(3,7,11-trimethyl-2,6,10-dodecatrienyl)-4,8,12-tetradecanrien-1-ol

To a stirred solution of 18.00 g (36.20 mmol) of Part B compound in 250mL ether at -70° C. under argon was added 1.37 g (36.20 mmol) of lithiumaluminum hydride. The reaction was stirred at -70° C. for 1 hour, thenat 0° C. for 4 hours. The reaction was quenched by the sequentialaddition of the following: a solution of 1.37 mL water in 28 mL oftetrahydrofuran (THF), 4.10 mL of a solution of 15% sodium hydroxide, asolution of 1.37 mL water in 28 mL of THF. The mixture was treated with10 g of magnesium sulfate, filtered through celite and concentrated toyield 13.89 g of a dark yellow oil. The crude product was purified byflash Chromatography on silica gel (1000 g) packed, loaded, and elutedwith 9:1 hexane/ethyl acetate. Pure fractions were combined andconcentrated to yield 8.05 g (49% yield from farnesyl bromide) of titlecompound as a clear oil.

TLC (Silica gel, 9:1 hexane/ethyl acetate) R_(f) =0.15.

MS (CI, NH₃, + ions) 472 (M+NH₄), 455 (M+H).

IR (CHCl₃ film) 3351, 2967, 2918, 2857, 1447, 1383, 1090, 1030, 835, 735cm⁻¹.

¹ H NMR (400 MHz, CDCl₃) δ5.17 (t, 2H, J=7.5 Hz) 5.10 (m, 4H) 3.52 (d,2H, J=5.5 Hz) 2.03 (m, 20H) 1.67 (s, 6H) 1.61 (s, 6H) 1.59 (s+m,13H)ppm.

D. (all-E)-5,9,13-Trimethyl-2-(3,7,11-trimethyl-2,6,10-dodecatrienyl)-4,8,12-tetradecatrien-1-yliodide

To a stirred solution of 7.98 g (17.50 mmol) of Part C alcohol and 107mg (2.5 mol %) of 4-dimethylaminopyridine in 50 mL methylene chloride at0° C. was added 3.18 mL (22.80 mmol) of triethylamine followed by 1.50mL (19.50 mmol) of methanesulfonyl chloride in 10.0 mL methylenechloride. The mixture was stirred at room temperature for 1 hour, whenit was diluted with 150 mL ether and 50 mL water. The aqueous fractionwas removed, the organic fraction was washed with brine, dried (sodiumsulfate), and concentrated to 9.20 g of a yellow oil. The crude productwas dissolved in 150 mL acetone and stirred with 7.89 g (52.60 mmol) ofsodium iodide in the dark at 65° C. for 30 hours. The acetone was thenremoved under vacuum and the resulting orange residue dissolved in 400mL hexane and 100 mL water. The aqueous fraction was removed and theorganic fraction was washed with saturated sodium sulfite (3×50 mL) andbrine, dried (sodium sulfate), and concentrated to leave 9.00 g of ayellow oil. The crude product was purified by flash chromatography onsilica gel (100 g) packed, loaded, and eluted with 4 L of 100% hexanefollowed by 4 L of 1:99 ethyl acetate/hexane. Pure fractions werecombined and concentrated to 7.91 g (80%) of title iodide as a clearoil.

TLC (Silica gel, 7:3 hexane/ethyl acetate) R_(f) =0.87.

MS (CI, NH₃, + ions) 582 (M+NH₄), 565 (M+H).

IR (CH₂ Cl₂ film) 2967, 2917, 2855, 1443, 1383, 1235, 1202, 1152, 1107,984, 833 cm⁻¹.

¹ H NMR (400 MHz, CDCl₃) δ5.09 (m, 6H) 3.23 (d, 2H, J=5.0 Hz) 2.03 (m,20H) 1.67 (s, 6H) 1.65 (s, 6H) 1.59 (s, 12H) 1.30 (m, 1H) ppm.

E.(all-E)-6,10,14-Trimethyl-3-(3,7,11-trimethyl-2,6,10-dodecatrienyl)-5,9,13-pentadecatrienenitrile

A stirred solution of 3.03 g (5.36 mmol) of Part D iodide and 0.80 g(16.10 mmol) of sodium cyanide in 30 mL of methylsulfoxide was heated to45° C. for 44 hours. The mixture was then diluted with 200 mL of a 1:1mixture of ether/hexane and washed with water and brine, dried (sodiumsulfate) and concentrated to 2.30 g of a clear oil. The crude productwas purified by flash chromatography on silica gel (300 g) packed,loaded, and eluted with 4:96 ethyl acetate/hexane. Pure fractions werecombined and concentrated to yield 2.07 g (83%) of title compound as aclear oil.

TLC (Silica gel, 7:3 hexane/ethyl acetate) R_(f) =0.76.

MS (CI, NH₃, + ions) 481 (M+NH₄), 464 (M+H).

IR (CH₂ Cl₂ film) 2967, 2918, 2855, 2245, 1669, 1445, 1383, 1107, 835,594 cm⁻¹.

¹ H NMR (400 MHz, CDCl₃) δ5.09 (m, 6H) 2.28 (d, 2H, J=5.5 Hz) 2.05 (m,20H) 1.75 (m, 1H) 1.68 (s, 6H) 1.64 (s, 6H) 1.60 (s, 12H) ppm.

F.(all-E)-6,10,14-Trimethyl-3-(3,7,11-trimethyl-2,6,10-dodecatrienyl)-5,9,13-pentadecatrien-1-ol

To a stirred solution of 4.70 g (10.10 mmol) of Part E nitrile in 10 mLof THF under argon at 0° C. was added 10.1 mL (15.2 mmol) of a 1.5Mdiisobutylaluminum hydride solution in toluene. The reaction was heatedto 40° C. for three hours when it was cooled to 0° C. and quenched bythe dropwise addition of 5 mL water. The mixture stirred at roomtemperature with 45 mL of 1M tartaric acid for two and a half hours,then was diluted with water (100 mL) and ether (400 mL). The aqueousfraction was removed and the organics washed with water and brine, dried(sodium sulfate), and concentrated to give 8.00 g of a clear oil.

The oil was dissolved in 20 mL of methanol and treated with 0.76 g(20.20 mmol) of sodium borohydride at 0° C. under argon for one hour.The reaction was quenched with 100 mL ammonium chloride and diluted with300 mL ether. The aqueous fraction was removed and the organics washedwith brine, dried (sodium sulfate), and concentrated to give 2.50 g of ayellow oil. The oil was purified by flash chromatography on silica gel(450 g) packed, loaded, and eluted with 9:1 hexane/ethyl acetate. Purefractions were combined and concentrated to yield 1.85 g (46% based on0.70 g of recovered Part D iodide starting material) of title alcohol asa clear oil.

TLC (Silica gel, CH₂ Cl₂) R_(f) =0.24.

¹ H NMR (270 MHz, CDCl₃) δ5.12 (m, 6H) 3.66 (t, 2H, J=7.0 Hz) 2.00 (m,21H) 1.67 (s, 6H) 1.59 (s+m, 21H) ppm.

G. (all-E)-6,10,14-Trimethyl-3-(3,7,11-trimethyl-2,6,10-dodecatrienyl)-5,9,13-pentadecatrien-1-yliodine

To a stirred solution of 2.05 g (4.37 mmol) of Part F alcohol in 15 mLof THF at 0° C. under argon was added 0.65 g (9.61 mmol) of imidazoleand 1.26 g (4.80 mmol) of triphenylphosphine, followed by the dropwiseaddition of 1.22 g (4.80 mmol) of iodine in 25 mL of THF. The mixturewas stirred at room temperature for 45 minutes when it was diluted withhexane (200 mL) and water (20 mL). The aqueous fraction was removed andthe organics were washed with saturated sodium sulfite and dried oversodium sulfate. The solution was absorbed onto 15 g of silica gel whichwas evaporated to dryness and loaded onto a column of 150 g of silicapacked with hexane. The product was eluted with 3.5 L of hexane followedby 1 L of 1:9 ethyl acetate/hexane. Pure fractions were combined andconcentrated to give 1.82 g (71%) of title iodide as a clear oil.

TLC (Silica gel, hexane) R_(f) =0.09.

MS (CI, NH₃, + ions) 596 (M+NH₄), 579 (M+H).

IR (CH₂ Cl₂ film) 2967, 2922, 2855, 1667, 1447, 1383, 1225, 1202, 1107,833 cm⁻¹.

¹ H NMR (300 MHz, CDCl₃) δ5.12 (m, 6H) 3.22 (t, 2H, J=7.5 Hz) 2.00 (m,20H) 1.80 (m, 2H) 1.73 (s, 6H) 1.62 (s+m, 19H) ppm.

H.(all-E)-1-(Diethoxyphosphinyl)-7,11,15-trimethyl-4-(3,7,11-trimethyl-2,6,10-dodecatrienyl)-6,10,14-hexadecatriene-1-sulfonicacid, cyclohexyl ester

To a stirred solution of 0.76 g (2.42 mmol) of Example 1A Part Bsulfonic acid, cyclohexyl ester in 2.0 mL of dimethylformamide (DMF) at0° C. under argon was added 52 mg (2.18 mmol) of sodium hydride. Aftergas evolution subsided, the mixture was brought to room temperature andstirred for 20 minutes when 0.68 g (1.17 mmol) of Part G iodide in 1.5mL of a 1:2 mixture of DMF/tetrahydrofuran was added. The mixture wasstirred for 69 hours and quenched with 30 mL of ammonium chloridesolution and diluted with 50 mL of ether. The aqueous fraction wasremoved and the organics were washed with brine. The combined aqueousfractions were back extracted with 25 mL of ether and the combinedorganics were dried (sodium sulfate) and concentrated to give 1.70 g ofa yellow oil. The crude product was purified by flash chromatography onsilica gel (100 g) packed and loaded with hexane, and eluted as with 1 Lof hexane followed by 2 L of 7:3 hexane/ethyl acetate. Pure fractionswere combined and concentrated to yield 0.19 g (21%) of title compoundas a colorless oil.

TLC (Silica gel, 7:3 hexane/ethyl acetate) R_(f) =0.25.

MS (CI, NH₃, + ions) 711 (M-C₆ H₁₀ +NH₃), 683 (711-C₂ H₄).

IR (neat) 2965, 2930, 2859, 1451, 1354, 1262, 1175, 1055, 1024, 972,930, 866, 828, 801 cm⁻¹.

¹ H NMR (400 MHz, CDCL₃) δ5.04 (m, 6H) 4.77 (m, 1H) 4.15 (m, 4H) 3.30(dt, 1H, J=20.0, 6.0 Hz) 1.95 (m, 24H) 1.75-1.32 (m, 8H) 1.60 (s, 6H)1.55 (s, 18H) 1.28 (t, 6H, J=7.5 Hz) ppm.

¹³ C NMR (100 MHz, CDCl₃) δ136.07 134.80 131.03 124.30 124.14 122.4882.37 63.25 (two d, J=6 Hz) 60.64 (d, J=138 Hz) 39.85, 39.62 39.20 32.6532.05 (d, J=5 Hz) 31.49 26.66 25.55 24.85 23.40 17.54 16.25 (d, J=5 Hz)16.11, 15.87, ppm.

I.(all-E-)-7,11,15-Trimethyl-1-phosphono-4-(3,7,11-trimethyl-2,6,10-dodecatrienyl)-6,10,14-hexadecatriene-1-sulfonicacid, tripotassium salt

To a solution of 190 mg (0.25 mmol) of Part H triester in 5 mL ofmethanol in a sealable tube was added ammonia gas at 0° C. untilsaturated. The tube was sealed and heated at 75° C. for 48 hours. Thetube was opened and the solution evaporated to a glassy oil which wasevaporated from toluene two times and dried under high vacuum, leavingan amber oil. The residue was dissolved in 3.5 mL of methylene chlorideand treated sequentially with 0.33 mL (1.25 mmol) ofbis(trimethylsilyl)trifluoroacetamide and 0.20 mL (1.50 mmol) oftrimethylsilyl bromide. The reaction mixture was stirred at roomtemperature under argon for 48 hours, at which point the volatiles wereremoved under vacuum and the remainder was dissolved in 1.50 mL (1.50mmol) of 1N KOH and lyophilized. The crude lyophilate was precipitatedby dissolving the sample in 2 mL of water, warming to 50° C., treatingthe solution with 2 mL of acetone and placing the mixture in an ice bathfor 0.5 h. The aqueous fraction was removed, the gummy solid wastriturated with ether and dried under vacuum. The solid was dissolved inwater and lyophilized to provide 89 mg (48%) of title compound as anoff-white solid.

TLC (Silica gel, 7:2:1 n-propanol/ammonia/water) R_(f) =0.13.

MS (FAB, + ions) m/e 779 (M+K), 742 (M+H), 703 (M+2H-K).

IR (KBr) 3443, 2969, 2924, 2857, 1678, 1451, 1400, 1383, 1208, 1090,1045, 968, 891, 835, 721 cm⁻¹.

¹ H NMR (400 MHz, CDCl₃) δ5.14 (t, 2H, J=7.0 Hz) 5.00 (m, 4H) 2.75 (m,1H) 1.90 (m, 22H) 1.58 (s+m, 6H) 1.54 (s, 6H) 1.50 (s, 6H) 1.48 (s, 6H)1.40 (m, 1H) ppm.

Anal. Calc'd for C₃₄ H₅₆ O₆ PSK₃ -2.28H₂ O-KOH: C, 48.71: H, 7.40; S,3.82; P, 3.69; Found C, 48.71; H, 7.47; S, 4.05; P, 3.91.

EXAMPLE 39

(E,E)-4-Hydroxy-6,10,14-trimethyl-1-phosphono-5,9,13-pentadecatriene-1-sulfonicacid, tripotassium salt

A. (E,E)-3,7,11-Trimethyl-2,6,10-dodecatrienal

To a CH₂ Cl₂ solution (15 mL) of oxalyl chloride (7.81 mL, 87.7 mmol)was added dimethyl sulfoxide (12.5 mL, 175.4 mmol) dropwise over 30 minat -60° C. The resulting clear solution was stirred at this temperaturefor 20 min. A solution of trans, trans- farnesol (Aldrich Chemical Co.)(15 g, 67.5 mmol) in CH₂ Cl₂ (325 mL) was added dropwise over 15 min.The reaction mixture became cloudy white during addition. Theheterogeneous reaction mixture was stirred at -60° C. for 30 min,whereupon triethylamine (56.4 mL, 405 mmol) was added dropwise over 10min. The reaction mixture became thick. The reaction mixture was allowedto warm to RT over 1 h. Ethyl ether (800 mL) was added and the organiclayer was washed with H₂ O (500 mL), brine (500 mL) and dried overMgSO₄. Evaporation gave 15 g (100%) of title compound as a crude oil.

B. (E,E)-3-Hydroxy-5,9,13-trimethyl-4,8,12-tetradecatrienoic acid,1,1-dimethylethyl ester

n-Butyllithium solution (32.4 mL, 2.5M in THF, 81.0 mmol) was addeddropwise to a solution diisopropylamine (11.35 mL, 81.0 mmol) in THF (20mL) at 0° C. After stirring 15 min, the reaction solution was cooled to-78° C. tert-Butyl acetate (7.07 mL, 84.3 mmol) in THF (50 mL) was addeddropwise and stirring was continued for 30 min. A solution of Part Acompound (15 g, 67.5 mmol) was added dropwise over 30 min and stirringwas continued at -78° C. for 1 h. Water (100 mL) was added and reactionmixture was warmed to RT. The reaction mixture was diluted with ethylacetate (500 mL) and the organic layer was washed with H₂ O (500 mL),brine (500 mL) and dried over MgSO₄. Evaporation gave a crude oil. Flashchromatography was performed on 1 kg silica gel, loaded and eluted with10:90 ethyl acetate/hexane. The pure fractions were combined andevaporated to give 16.0 g (71%) of title compound as a yellowish oil.

C.(E,E)-5,9,13-Trimethyl-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,8,12-tetradecatrienoicacid, 1,1-dimethylethyl ester

tert-Butyldimethylsilyl chloride (2.96 g, 19.7 mmol) was added to amixture of Part B compound (6.0 g, 17.9 mmol) and imidazole (1.58 g,23.2 mmol) in DMF (50 mL) at RT. The reaction mixture was stirred at RTfor 2 h, then partitioned between ethyl ether (800 mL) and H₂ O (500mL). The aqueous layer was extracted with ethyl ether (200 mL). Thecombined organic layers were washed with H₂ O (2×500 mL), brine (2×500mL) and dried over MgSO₄. Evaporation gave 8.01 g (100%) of titlecompound as a crude oil.

D. (E,E)-5,9,13-Trimethyl-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,8,12-tetradecatrien-1-ol

Diisobutylaluminum hydride solution (39.3 mL, 1M in toluene, 39.3 mmol)was added dropwise to a solution of Part C compound (8.0 g, 17.9 mmol)in toluene (70 mL) at 0° C. under argon. Stirring was continued for 1.5h. Methanol (5 mL) was added until bubbling ceased. A 1M potassiumsodium tartrate solution (300 mL) was added and vigrous stirring wasbegun. After a few minutes the reaction mixture gelatinized. Stirringwas continued for 1 h. Ethyl acetate (500 mL) was added and the organiclayer was washed with brine (500 mL), then dried over MgSO₄. Evaporationgave a pale yellow oil. Purification was performed by flashchromatography on 750 g silica gel, loaded and eluted with 10% ethylacetate in hexane. Pure fractions were combined and evaporated to give4.5 g (65%) of title compound as a colorless oil.

E. (E,E)-5,9,13-Trimethyl-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,8,12-tetradecatrien-1-yliodide

To a mixture of Part D alcohol (4.50 g, 11.84 mmol), triphenylphosphine(3.40 g, 13.0 mmol) and imidazole (1.60 g, 23.7 mmol) in THF (30 mL), asolution of iodine (2.83 g, 13.0 mmol) in THF (5 mL) was added dropwiseat RT. After stirring for 20 min, hexane (300 mL) was added to dilutethe reaction mixture. The organic layer was washed with 10% sodiumbisulfite (100 mL), saturated sodium bicarbonate (300 mL), brine (300mL) and dried over MgSO₄. The filtrate was evaporated to a volume of 100mL, silica gel (10 g) was added and evaporation was continued todryness. Flash chromatography was performed on 500 g silica gel, loadedand eluted with 1:99 ethyl acetate/hexane. Pure fractions were combinedand evaporated to give 5.2 g (90%) of title compound as a colorless oil.

F.(E,E)-1-(Diethoxyphosphinyl)-6,10,14-trimethyl-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5,9,13-pentadecatriene-1-sulfonicacid, cyclohexyl ester

To a suspension of sodium hydride (0.51 g, 1.22 mmol) in DMF (12 mL)under argon, a solution of Example 1A Part B sulfonate (8.3 g, 26.53mmol) in DMF (12 mL) was added dropwise over 10 min at 100° C. (icebath). The ice bath was removed and the reaction mixture was stirred atRT until the reaction solution was clear. The reaction was recooled to0° C., and a solution of Part E compound (5.2 g, 10.61 mmol) in DMF (12mL) was added dropwise over 15 min. Stirring was continued for 2 h. Thereaction mixture was warmed to RT and stirring was continued overnight.Diethyl ether (300 mL) was added to dilute reaction solution. Theorganic layer was washed with H₂ O (200 mL), brine (200 mL) and driedover MgSO₄. Evaporation gave a crude oil. Flash chromatography wasperformed on 450 g silica gel, loaded and eluted with 10:90isopropanol/hexane. Pure fractions were combined and evaporated to give4.8 g (70%) of title compound as a colorless oil.

G.(E,E)-1-(Diethoxyphosphinyl)-4-hydroxy-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, cyclohexyl ester

A stock HF/pyridine(Py)/THF solution was prepared by combiningcommercial HF_(x).p_(y) (2 mL) and dry pyridine (4 mL) in THF (14 mL).

Part F compound (4.8 g, 7.10 mmol) was dissolved in a stock solution ofHF/Py/THF (200 mL) at RT. The reaction mixture was stirred at RTovernight. Ethyl acetate (500 mL) was added and the organic layer waswashed with H₂ O (100 ML), 1N HCl (100 mL), saturated sodium bicarbonate(100 mL), brine (100 mL) and dried over MgSO4. Evaporation gave a crudeoil. Flash chromatogrophy was performed on 300 g silica gel, loaded andeluted with 1:1 ethyl acetate/hexane. Pure fractions were combined andevaporated to give 1.85 g (68%) of title compound as a colorless oil.

H.(E,E)-4-Hydroxy-6,10,14-trimethyl-1-phosphono-5,9,13-pentadecatriene-1-sulfonicacid, tripotassium salt

To a solution of Part G compound (1.00 g, 1.79 mmol) in methanol (20 mL)was bubbled anhydrous ammonia gas until the solution was saturated. Thenthe sealed tube containing the reaction mixture was heated in an oilbath (70° C.) overnight. The reaction mixture was evaporated to dryness.Purification was performed by chromatography on CHP20P gel (2.5×20 cm),loaded and eluted with water followed by gradual addition of CH₃ CN to areservoir of water. The pure fractions were combined, evaporated andazeotroped with toluene. To a stirred solution of the resulting residue(780 mg, 1.57 mmol) and collidine (1.03 mL, 7.85 mmol) indichloromethane (10 mL) at RT under argon was added bromotrimethylsilane(1.66 mL, 12.56 mmol). The mixture was stirred at RT for 20 h. Thesolvent was evaporated and the residue was pumped at high vacuum for 2h. The residue was dissolved in 1M potassium hydroxide (10 mL, 10 mmol)and the reaction mixture was stirred for 2 h. The solution waslyophilized to give a white solid. The crude product was purified bychromatography on CHP20P gel (2.5×20 cm), loaded and eluted with waterfollowed by gradual addition of CH₃ CN to a reservoir of water. Thecombined pure fractions were evaporated to remove CH₃ CN and theremaining aqueous solution was precipitated with acetone to provide 220mg (30%) of title compound as a white solid.

IR (KBr) 2924, 1661, 1198, 1082, 964 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ5.07-5.03 (m, 3H) 4.31-4.26 (m, 1H) 2.74 (m,1H) 1.98-1.80 (m, 8H) 1.78-1.60 (m, 4H) 1.55 (s, 3H) 1.53 (s, 3H) 1.47(s, 6H) ppm.

¹³ C NMR (D₂ O, 100 MHz) δ139.76,139.58 136.54 133.42 126.59, 126.52124.56 68.78, 67.92 61.41 (dd, J=120 Hz) 38.99 38.94 37.09 (d, J=7 Hz)25.97 24.98 24.55 17.07 16.02 15.36 ppm.

MS (FAB, + ions) m/z 521 [(M+H)-H₂ O], 539 (M+H), 577 (M+K).

Anal. Calcd for C₁₈ H₃₀ K₃ O₇ PS.1.0 H₂ O: C, 38.83; H, 5.79; P, 5.56;S, 5.76 Found: C, 38.85; H, 5.84; P, 5.33; S, 5.57.

EXAMPLE 40

3-Phenoxy-α-phosphonobenzenebutanesulfonic acid, tripotassium salt

A. (E)-3-(3-Phenoxyphenyl)-2-propenoic acid, ethyl ester

Triethyl phosphonoacetate (6.5 mL, 32.8 mmol) was added dropwise to asuspension of sodium hydride (0.73 g, 30.2 mmol) in THF (40 mL) at 0° C.under argon. The ice bath was removed and the suspension was stirred atRT for 20 min, at which time a clear colorless solution resulted. Thereaction solution was recooled to -78° C. and a solution of3-phenoxybenzaldehyde (5.0 g, 25.2 mmol) in THF (10 mL) was addeddropwise. The reaction mixture was stirred an -78° C. for 45 min. Afterwarming to RT, the reaction was quenched with saturated ammoniumchloride solution. Diethyl ether (200 mL) was added, the organic layerwas washed with H₂ O (50 mL), brine (50 mL) and dried over MgSO₄.Evaporation gave 4.0 g of title ester (96%) as a colorless oil.

B. 3-Phenoxybenzenepropanoic acid, ethyl ester

A mixture of Part A ester (6.5 g, 24.3 mmol) and palladium on carbon(10%, 300 mg) in ethyl acetate (50 mL) was stirred under a hydrogenatmosphere (balloon) overnight at RT. The reaction mixture was filteredthrough Celite. Evaporation of filtrate gave a crude oil. Purificationwas performed by flash chromatography on 400 g silica gel, loaded andeluted with 10% ethyl acetate in hexane. Pure fractions were combinedand evaporation gave 5.45 g of title ester (84%) as a colorless oil.

C. 3-Phenoxybenzenepropanol

Lithium aluminum hydride solution (20.5 mL, 1M in THF, 20.5 mmol) wasadded dropwise to a solution of Part B ester (5.45 g, 20.5 mmol) in THF(50 mL) at 0° C. under argon. Stirring was continued for 10 min. Ethylacetate (5 mL) was added until bubbling ceased. Ethyl ether (300 mL) wasadded and the organic layer was washed with 1N HCl solution (2×150 mL),H₂ O (150 mL), saturated sodium bicarbonate (150 mL), and brine (150mL), then dried over MgSO₄. Evaporation gave a pale yellow oil.Purification was performed by flash chromatography on 500 g silica gel,loaded and eluted with 15% ethyl acetate in hexane. Pure fractions werecombined and evaporated to give 4.2 g of title alcohol (90%) as acolorless oil.

D. 1-(3-Iodopropyl)-3-phenoxybenzene

Iodine (1.80 g, 7.24 mmol) in THF (5 mL) was added to a mixture of PartC alcohol (1.5 g, 6.58 mmol), triphenylphosphine (1.90 g, 7.24 mmol) andimidazole (0.89 g, 13.2 mmol) in THF (15 mL). The reaction mixture wasstirred at RT for 20 min, then diluted with hexane (200 ml). The organiclayer was washed with 10% sodium bisulfite (50 mL), saturated sodiumbicarbonate (50 mL), brine (50 mL) and dried over MgSO₄. The solvent wasevaporated to 100 ml volume, 10 g silica gel was added and the mixturewas evaporated to dryness. Flash chromatography was performed on 100 gsilica gel, loaded and eluted with hexane. Pure fractions were combinedand evaporated to give 1.70 g of title iodide (76%) as a colorless oil.

E. 3-Phenoxy-α-(diethoxyphosphinyl)benzenebutanesulfonic acid,cyclohexyl ester

To a stirred suspension of sodium hydride (241 mg, 10.1 mmol) in DMF (10mL) at 0° C. under argon, Example 1A Part B sulfonate (3.95 g, 12.6mmol) in DMF (4 mL) was added dropwise over 15 min. The ice bath wasremoved and the reaction mixture was stirred at RT for 30 min. Thereaction mixture was recooled to 0° C. and a DMF solution (10 mL) ofPart D iodide (1.7 g, 5.03 mmol) was added dropwise over 15 min. Themixture was stirred at 0° C. for 2 h. The ice bath was removed and thereaction mixture was stirred at RT overnight. The mixture was dilutedwith 300 ml of Et₂ O and washed with H₂ O (150 ml), brine (150 mL) anddried over MgSO₄. Evaporation gave a crude oil. Purification wasperformed by flash chromatography on 100 g silica gel, loaded and elutedwith 25% ethyl acetate in hexane. The pure fractions were combined andevaporated to provide 1.5 g of title compound (57%) as a colorless oil.

F. 3-Phenoxy-α-phosphonobenzenebutanesulfonic acid, tripotassium salt

Ammonia gas was bubbled through a solution of Part E compound (1.20 g,2.23 mmol) in methanol (20 mL) until the solution was saturated. Thesealed tube was heated at 70° C. overnight. The reaction mixture wascooled to RT, evaporated to dryness and azeotroped with toluene. To astirred solution of the resulting residue in dichloromethane (10 mL) atRT under argon was added bromotrimethylsilane (2.6 mL, 19.6 mmol). Themixture was stirred at RT for 20 h. The solvent was evaporated and theresidue was pumped at high vacuum for 2 h. The residue was dissolved in1M potassium hydroxide (10 mL, 10 mmol) and the reaction mixture wasstirred for 2 h. The solution was lyophilized to give a white solid. Thecrude product was purified by chromatography on CHP20P gel (2.5×20 cm),loaded and eluted with water and followed by a gradient created by thegradual addition of CH₃ CN to a reservior of water. The combined purefractions were concentrated to about 5 mL volume then lyophilized toprovide 780 mg (47%) of title compound as a white solid.

IR (KBr) 2957, 1613, 1595, 1489, 1250, 1202, 1074, 966 cm⁻¹

¹ H NMR D₂ 0, 400 MHz) δ7.29 (t, 2H, J=7.5 Hz) 7.21 (t, 1H, J=8.4 Hz)7.07 (t, 1H, J=7.4 Hz) 6.99 (d, 1H, J=7.7 Hz) 6.95 (d, 2H, J=7.7 Hz)6.86 (s, 1H) 6.76 (d, 1H, J=8.1 Hz) 2.76 (dt, 1H, J=6,18 Hz) 2.65-2.45(m, 2H) 1.98-1.65 (m, 4H) ppm.

¹³ C NMR (D₂ O, 100 MHz) δ157.03, 156.87, 145.87, 130.24, 130.05,124.05, 123.95, 119.09, 118.91, 116.11, 61.70, (d, J=120 Hz) 35.46,31.38, (d, J=7 Hz) 19.67 ppm.

Mass Spec (FAB, + ions) m/z 463 (M-K+2H), 501 (M+H), 539 (M+K).

Anal. Calc'd for C₁₆ H₁₆ K₃ O₇ PS. 1.8 equiv H₂ O: C, 36.05; H, 3.71; P,5.81; S, 6.01. Found: C, 36.05; H, 3.97; P, 5.58; S, 6.06.

EXAMPLE 41

(E,E)-1-[Bis[(2,2-Dimethyl-1-oxopropoxy)methoxy]phosphinyl]-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, cyclohexyl ester

A. 2,2-Dimethylpropanoic acid, iodomethyl ester

Sodium iodide (dried) (15.0 g, 100 mmol) was added in one portion to asolution of 2,2-dimethylpropanoic acid, chloromethyl ester (10.0 g, 66.7mmol) in dry acetonitrile (80 mL) at RT under argon. The heterogeneousreaction was stirred at RT for 6 h, then concentrated in vacuo. Theresidue was partitioned between toluene (150 mL) and 5% sodium bisulfite(40 mL). The organic layer was washed with 5% sodium bisulfite (40 mL)and water (20 mL), then dried over MgSO₄. Evaporation gave title iodide(12.1 g, 75%) as a pale yellow oil.

B. (E,E)-1-Phosphono-6,10,14-trimethylpentadecatriene-1-sulfonic acid,cyclohexyl ester, disilver salt

Bromotrimethylsilane (1.45 mL, 11.0 mmol) was added dropwise to asolution of Example 1A Part C sulfonate (1.50 g, 2.75 mmol) and allyltrimethylsilane (4.36 mL, 27.5 mmol) in CH₂ Cl₂ (5 mL) at RT underargon. The clear yellow reaction was stirred at RT for 52 h,concentrated in vacuo, then pumped at high vacuum overnight to give anorange oil.

The crude silyl ester prepared above was dissolved in 1N KOH (6.05 mL,6.05 mmol) over 15 min, then added dropwise over 5 min to a solution ofsilver nitrate (1.17 g, 6.88 mmol) in water (100 mL) under argon in thedark (A1 foil). The resultant tan suspension was stirred at RT for 10min, then the reaction mixture was lyophilized to give a tan solid. Thelyophilate was partitioned between toluene (50 mL) and water (50 mL).The aqueous layer was extracted with toluene (3×50 mL). The combinedorganic extracts were washed with water containing a few drops of brine(20 mL), then dried over Na₂ SO₄. Evaporation followed by pumping underhigh vacuum for 30 min gave title compound (1.91 g, 99%) as a brown gum.

C. (E,E)-1-[Bis[(2,2-Dimethyl-1-oxo-propoxy)methoxy]phosphinyl-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, cyclohexyl ester

A solution of Part B compound (1.91 g, 2.71 mmol) in toluene (20 mL) wascooled to 0° C. under argon. A solution of Part A ester (1.66 g, 6.88mmol) in toluene (5 mL) was added to the brown solution over 5 min.After 5 min at 0° C., a solid precipitated out of solution. The reactionwas stirred an additional 15 min, then filtered through a 0.45 μmfilter. The filtrate was concentrated in vacuo to give a pale yellowoil, which was purified by flash chromatography on silica gel (100 g)eluting with 15:85 EtOAc/hexane to provide title compound (1.34 g, 67%)as a colorless oil.

TLC (20:80 EtOAC/hexane): R_(f) =0.21

IR (neat) 2965, 2936, 1757, 1134, 959 cm⁻¹.

¹ H NMR (CDCl₃, 400 MHz) δ5.74 (m, 4H) 5.10 (m, 3H) 4.85 (m, 1H) 3.57(dt, 1H) 2.23-1.88 (m, 14H) 1.88-1.47 (m, 7H) including 1.68 (s, 3H)1.60 (s, 9H) 1.47-1.13 (m, 3H) including 1.24 (s, 18H) ppm.

¹³ C NMR (CDCl₃, 100 MHz) δ176.69 176.63 136.14 134.91 131.12 124.33124.10 122.96 83.17 82.30 (d, J=6 Hz) 82.09 (d, J=6 Hz) 60.30 (d, J=139Hz) 39.68 38.66 32.60 27.95 (d, J=6 Hz) 27.49 26.78 26.71 26.66 26.4425.61 24.84 23.32 17.60 16.04 15.90 ppm.

MS (CI, NH₃) m/z 736 (M+NH₄).

Anal. Calc'd for C₃₆ H₆₃ O₁₀ PS: C, 60.15; H, 8.83; P, 4.31; S, 4.46.Found: C, 60.08; H, 9.03; P, 4.47; S, 4.18.

EXAMPLE 42

(E,E)-1-[Bis[(2,2-Dimethyl-1-oxopropoxy)methoxy]phosphinyl]-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, monopotassium salt

Potassium acetate (403 mg, 4.11 mmol) was added to a solution of Example41 compound (982 mg, 1.37 mmol) in 2,2,2-trifluoroethanol/water (10:1,10 mL) at RT under argon. After dissolution, the clear colorlessreaction was heated an 40° C. overnight (18 h), then concentrated invacuo. The slightly colored oil was dissolved in EtOAc (30 mL) andwashed with saturated KHCO₃ (2×5 mL) and half-saturated KCl (10 mL). Theorganic layer was dried over anhydrous KCl. Evaporation followed bypumping under high vacuum overnight gave title salt (893 mg, 97%) as acolorless oil.

TLC (10:90 MeOH/CH₂ Cl₂) : R_(f) =0.18

IR (neat) 2969, 2920, 1755, 1248, 1136, 1005 cm⁻¹.

¹ H NMR (DMSO, 400 MHz) δ5.59 (d, 2H, J=12.6 Hz) 5.56 (d, 2H, J=12.4 Hz)5.08 (m, 3H) 2.98 (dt, 1H, J=6.2, 19.7 Hz) 2.08-1.68 (m, 12H) 1.63 (s,3H) 1.56 (s, 9H) 1.55-1.45 (m, 2H) 1.17 (s, 9H) 1.16 (s, 9H) ppm.

¹³ C NMR (CD₃ OD, 100 MHz) δ178.42 178.21 136.48 135.84 131.99 125.46125.07 83.69 (d, J=5.9 Hz) 83.33 (d, J=5.9 Hz) 60.31 (d, J=138 Hz) 40.8640.80 39.75 29.52 (d, J=7.4 Hz) 28.83 28.51 27.79 27.74 27.33 25.9317.83 16.31 16.18 ppm.

MS (FAB, + ions) m/z 713 (M+K), 675 (M+H).

Anal. Calc'd for C₃₀ H₅₂ KO₁₀ PS: C, 53.39; H, 7.77; P, 4.59; S, 4.75.Found: C, 53.30; H, 7.81; P, 4.84; S, 5.19.

EXAMPLE 43

α-Phosphono[1,1':4', 1"-terphenyl]-4"-butanesulfonic acid, tripotassiumsalt

A. 4-Aminobenzenepropanoic acid, ethyl ester

A 500 mL Parr hydrogenation vessel was charged with 12.36 g (55.9 mmol)of (E)-3-(4-nitrophenyl)-2-propenoic acid, ethyl ester, 100 mL ofabsolute ethanol, 15 mL of concentrated hydrochloric acid and 0.75 g of10% palladium-on-activated charcoal. The slurry was purged with nitrogenand then agitated under an initial pressure of 44.5 psi of hydrogen gas.After 16 h, 18.5 psi had been consumed. The flask was evacuated, purgedagain with nitrogen and the contents filtered through Celite andevaporated. The residue was dissolved in water and adjusted to pH 9 withsolid sodium carbonate. The resulting mixture was extracted thrice withdichloromethane, and the combined organic extracts dried over Na₂ SO₄,filtered and evaporated to provide 9.31 g, 86% of title compound as ayellow oil, sufficiently pure for use in subsequent reactions.

B. 4-Iodobenzenepropanoic acid, ethyl ester

To a stirred solution of 6.48 g (33.6 mmol) of Part A amine in 10 mL(120 mmol) of diiodomethane under nitrogen at room temperature was added9 mL (67 mmol) of isoamyl nitrite over 10 min. The orange solution wasstirred for 30 min and then heated to 80° C. for 2 h. The deep orangesolution was diluted with ether and washed once with 2M HCl, once withwater, once with saturated sodium bicarbonate solution and once withsaturated sodium bisulfite solution. The organic phase was dried (MgSO₄)and evaporated. Purification by flash chromatography on silica gel (5×20cm column) eluted with 3:2 hexanes/dichloromethane gave title iodide asa colorless oil, 8.65 g, 85% yield.

C. [1,1':4',1"-Terphenyl]-4-propanoic acid, ethyl ester

To a stirred solution of 1.17 g (5.0 mmol) of 4-bromobiphenyl in 10 mLof THF at -75° C. under argon was added 5.9 mL (10.0 mmol, 1,7M inpentane) of t-butyllithium dropwise over 15 min. After an additional 15min, the blue-green solution was warmed to 0° C., stirred 30 min and asolution of 1.86 g (14 mmol) thrice-fused zinc chloride in 15, mL of THFwas added. The resulting colorless, turbid solution was stirred for 1 hand then a solution of 1.00 g (3.3 mmol) of Part B iodide and 0.3 g(0.26 mmol) of tetrakis(triphenylphosphine)palladium(0) in 5 mL of THFwas added. The reaction was stirred for 16 h, diluted with ether andwashed once with 10% citric acid. The organic phase was dried (MgSO₄)and evaporated. Purification by flash chromatography on silica gel (5×15cm column) eluted with 11:9 hexanes/dichloromethane gave title ester asan off-white solid, 1.07 g, 98% yield, mp 172°-174° C.

D. [1,1:4',1"-Terphenyl]-4-propanol

To a stirred solution of 1.00 g (3.0 mmol) of Part C ester in 5 mL ofTHF under nitrogen at room temperature was added 3 mL (3 mmol) of 1Mlithium aluminium hydride in THF. The reaction was stirred for 1 h,quenched with brine and brought to pH 1 with 2N H₂ SO₄. Extracted thricewith 100 mL portions of ethyl acetate. The organic extracts werecombined, dried (MgSO₄) and evaporated to give title alcohol as grayflakes, mp 210°-212° C., 740 mg, 86% yield. The compound was usedwithout further purification.

E. 4-(3-Iodopropyl) [1,1':4',1"-terphenyl]

To a stirred solution of 720 mg (2.50 mmol) of Part D title alcohol, 660mg (2.51 mmol) of triphenylphosphine, and 375 mg (5.5 mmol) of imidazolein 20 mL of THF under argon at room temperature was added a solution of640 mg (2.5 mmol) of iodine in 5 mL of THF, dropwise over 20 min. Afteraddition was complete, the reaction was diluted with hexanes and washedonce with saturated sodium bisulfite solution. The organic phase wasdried (MgSO₄) and evaporated. Purification by flash chromatography onsilica gel (5×10 cm column) eluted with CH₂ Cl₂ gave title iodide as awhite solid, 860 mg, 86% yield.

F. α-(Diethoxyphosphinyl) [1,1':4',1"-terphenyl]-4-butanesulfonic acid,cyclohexyl ester

To a stirred slurry of 145 mg (3.6 mmol, 60% mineral oil dispersion) ofsodium hydride in 3 mL of DMF under argon at -10° C. was added asolution of 1.26 g (4.0 mmol) of Example 1A Part B sulfonate in 2 mL ofDMF. After addition was complete, the reaction was warmed to roomtemperature and stirred for 30 min. To the resulting solution was added800 mg (2.00 mmol) of Part E title iodide as a powdered solid. Thereaction mixture was diluted with 1.5 mL of THF to form a turbid slurry.The reaction was stirred for 16 h, diluted with 100 mL of ether andwashed once with 10% citric acid and thrice with water. The organicphase was dried (MgSO₄) and evaporated. Purification by flashchromatography on silica gel (5×15 cm column) eluted with 1:19ether/dichloromethane gave title compound as a colorless oil, 620 mg,53% yield.

G. α-Phosphono[1,1':4',1"-terphenyl]-4"-butanesulfonic acid,tripotassium salt

To a stirred solution of 590 mg (1 mmol) of Part F compound in 7 mL ofdichloromethane under argon at room temperature was added 420 μL (3mmol) of bromotrimethylsilane. After 24 h, the resulting clear solutionwas evaporated at 25° C. and the residue dissolved in 10 mL of THF. Tothis stirred solution was added 550 mg (3.3 mmol) of dried, finelyground potassium iodide and 5 mg (0.015 mmol) of 18-crown-6. Theresulting slurry was heated to reflux for 24 h, evaporated and thenstirred for 1 h with 6 mL (3 mmol) of 0.5M potassium hydroxide solution.The solution was lyophilized and then purified by MPLC (2.5×20 cm columnof Mitsubishi Kasei Sepabeads CHP20P resin): 11.5 mL fractions, 7 mL/minflow rate, eluted with 140 mL water and then a gradient of 500 mL 3:2acetonitrile/H₂ O into 450 mL H₂ O). Fractions 41-49 were collected andlyophilized to give title compound as a white solid, 480 mg, 78% yield.

IR (KBr pellet) 3407, 3092, 2932, 2864, 1634, 1485, 1198, 1078, 1049,966 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ8.03 (br s, 6H) 7.93 (d, 2H, J=6.8 Hz) 7.80(dd, 2H, J=6.9, 6.4 Hz) 7.71 (d, 4H, J=6.4 Hz) 2.97 (dt, 1H, J=6, 18 Hz)2.21 (m, 2H) 2.21 (m, 4H) ppm.

Anal. Calc'd for C₂₂ H₂₀ K₃ O₆ PS.3.1 H₂ O: C, 42.83; H, 4.29; P, 5.02;S, 5.20 Found: C, 42.83; H, 4.19; P, 5.03; S, 5.18.

MS (FAB, + ions) m/e 561 (M+H), 523 (M-K+2H), 485 (M-2K+3H).

EXAMPLE 44

4-(2-Methylphenoxy)-α-phosphonobenzenebutanesulfonic acid, tripotassiumsalt

A. 4-(2-Methylphenoxy)benzenepropanoic acid, ethyl ester

To a suspension of sodium hydride (155 mg, 6.44 mmol) in pyridine (25mL) was added a solution of the iodide prepared as described in Example43 Part B (696 mg, 6.44 mmol) in pyridine (2.5 mL) at 0° C. under argon.Stirring was continued until the solution was clear (15 min). Thereaction was warmed to RT, and a solution of o-cresol (990 mg, 3.22mmol) in pyridine (2.5 mL) was added to the reaction followed by copperbromide-dimethyl sulfide complex (2.0 g, 9.66 mmol). The reaction wasrefluxed for 2.5 h. The reaction was evaporated to dryness. Ethyl ether(200 mL) was added to dilute the reaction, and the organic layer waswashed with 1N HCl (2×50 mL), water (2×50 mL), saturated sodiumbicarbonate solution (50 mL), brine (50 mL) and dried over MgSO₄.Purification was performed by flash chromatography on 200 g silica gel,loaded and eluted with 10% ethyl acetate in hexane. Pure fractions werecombined and evaporated to give title compound (650 mg, 72%) as acolorless oil.

B. 4-(2-Methylphenoxy)benzeneoropanol

Lithium aluminum hydride solution (2.32 mL, 1M in THF, 2.32 mmol) wasadded dropwise to a solution of Part A ester (650 mg, 2.32 mmol) in THF(50 mL) at 0° C. under argon. Stirring was continued for 10 min. Ethylacetate (5 mL) was added to destroy excess lithium aluminum hydride(LAH). Ethyl ether (200 mL) was added and the organic layer was washedwith 1N HCl solution (2×50 mL), H₂ O (50 mL), saturated sodiumbicarbonate solution (50 mL), and brine (50 mL), then dried over MgSO₄.Evaporation gave title compound (350 mg, 62%) as a colorless oil.

C. 1-(3-Iodopropyl)-4-(2-methylphenoxy)benzene

A solution of iodine (399 mg, 1.57 mmol) in THF (5 mL) was added to amixture of Part B alcohol (345 mg, 1.43 mmol), triphenylphosphine (411mg, 1.57 mmol) and imidazole (194 mg, 2.86 mmol) in THF (15 mL). Thereaction mixture was stirred at RT for 10 min, then diluted with hexane(200 ml). The organic layer was washed with 10% sodium bisulfite (50mL), saturated sodium bicarbonate (50 mL), brine (50 mL) and dried overMgSO₄. The solvent was evaporated to 100 ml volume, 6 g silica gel wasadded, and the mixture was evaporated to dryness. Flash chromatographywas performed on 100 g silica gel, loaded and eluted with hexane. Purefractions were combined and evaporated to give title iodide (400 mg,76%) as a colorless oil.

D. α-(Diethoxyphosphinyl)-4-(2-methylphenoxy)benzenebutanesulfonic acid,cyclohexyl ester

To a stirred suspension of sodium hydride (54.7 mg, 2.28 mmol) in DMF (5mL) at 0° C. under argon, Example 1A Part B sulfonate (895 mg, 2.85mmol) in DMF (2 mL) was added dropwise over 15 min. The ice bath wasremoved and the reaction mixture was stirred at RT for 30 min. Thereaction mixture was recooled to 0° C. and a solution of Part C iodide(400 mg, 1.14 mmol) in DMF (2 mL) was added dropwise over 15 min. Themixture was stirred at 0° C. for 2 h. The ice bath was removed and thereaction mixture was stirred at RT overnight. The mixture was dilutedwith ethyl ether (150 mL) and washed with H₂ O (50 ml), brine (50 mL)and dried over MgSO₄. Evaporation gave a crude oil. Purification wasperformed by flash chromatography on 150 g silica gel, loaded and elutedwith 25% ethyl acetate in hexane. The pure fractions were combined andevaporated to provide title compound (450 mg, 73%) as a colorless oil.

E. 4-(2-Methylphenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt

Ammonia gas was bubbled through a solution of Part D compound (450 mg,0.84 mmol) in methanol (10 mL) until the solution was saturated. Thesealed tube was heated at 70° C. overnight. The reaction mixture wascooled to RT, evaporated to dryness and azeotroped with toluene (2×20mL). To a stirred solution of the resulting residue in dichloromethane(10 mL) at RT under argon was added bromotrimethylsilane (0.77 mL, 5.86mmol). The mixture was stirred at RT for 20 h. The solvent wasevaporated and the residue was pumped at high vacuum for 2 h. Theresidue was dissolved in 1M potassium hydroxide (5 mL, 5 mmol) and thereaction mixture was stirred for 2 h. The solution was lyophilized togive a white solid. The crude product was purified by chromatography onCHP20P gel (2.5×20 cm), loaded and eluted with water and followed by agradient created by the gradual addition of CH₃ CN to a reservior ofwater. The combined pure fractions were concentrated to about 5 mLvolume then lyophilized to provide title compound (370 mg, 72%) as awhite solid.

TLC (n-propanol/NH₄ OH/H₂ O=5:4:1) (silica gel) (R_(f) =0.26)

IR (KBr) 2951, 2932, 1653, 1507, 1240, 1204, 1076, 966, 878 cm⁻¹

¹ H NMR (D₂ O, 400 MHz) δ7.22 (d, 1H, J=6.8 Hz) 7.14 (d, 2H, J=8.6 Hz)7.10 (t, 1H, J=7.7 Hz) 7.03 (t, 1H, J=6.8 Hz) 6.84 (d, 1H, J=8.1 Hz)6.74 (d, 2H, J=8.5 Hz) 2.78 (dt, 1H, J=5.3,18.0 Hz) 2.49 (m, 2H) 2.07(s, 3H) 1.99-1.61 (m, 4H) ppm.

¹³ NMR (D₂ O, 100 MHz) δ155.59 154.19 137.88 131.73 130.47 130.03 127.58124.76 120.22 117.09 61.63 (d, J=118 Hz) 35.65 31.55 (d, J=8 Hz) 28.5715.33 ppm.

MS (FAB, + ions) m/z 477 (M-K+2H), 515 (M+H), 553 (M+K).

Anal. Calcd for C₁₇ H₁₈ K₃ O₇ PS 2.3 equiv H₂ O: C, 36.72; H, 4.10; P,5.57; S, 5.77. Found: C, 36.72; H, 3.91; P, 5.51; S, 5.54.

EXAMPLE 45

3-(3-Propylphenoxy)-α-phosphonobenzenebutanesulfonic acid, tripotassiumsalt

A. 3-Iodobenzenepropanoic acid, ethyl ester

(1). (E)-3-(3-Nitrophenyl)-2-propenoic acid, ethyl ester

A mixture of 3-nitrocinnamic acid (11.7 g, 60.6 mmol), concentratedsulfuric acid (0.16 mL, 3.03 mmol) and absolute ethanol (120 mL) wasrefluxed overnight. The reaction mixture was poured into ice water (400mL). The mixture was extracted with ethyl ether (500 mL×2). The organiclayer was washed with saturated sodium bicarbonate solution (100 mL×2),water (100 mL×2), brine (100 mL×2) and dried over magnesium sulfate.Evaporation gave title compound (12.0 g, 99%) as a colorless oil.

(2) 3-Aminobenzenepropanoic acid, ethyl ester

A Parr hydrogenation vessel was charged with Part (1) compound (12.0 g,54.3 mmol), concentrated HCl (15 mL, 0.15 mmol), 10% palladium on carbon(750 mg) and absolute ethanol (75 mL). The slurry was purged withnitrogen and agitated under an initial pressure of 45 psi of hydrogengas. After 16 h, the flask was evacuated and the contents filteredthrough Celite and evaporated. The residue was dissolved in water andadjusted to pH 9 with solid sodium carbonate. The resulting mixture wasextracted with dichloromethane (250 mL×2). The combined extracts wereevaporated to give the title compound (8.7 g, 86%) as an oil.

(3) 3-Iodobenzenepropanoic acid, ethyl ester

To a solution of Part (2) compound (7.2 g, 32 mmol) in diiodomethane(10.3 mL, 128 mmol) under argon at RT was added isoamyl nitrite (6.5 mL,64 mmol) over 10 min. The brownish solution was stirred at RT for 40 minand then heated to 80° C. for 2 h. Ethyl ether (300 mL) was added to thereaction and the organic layer was washed with 1N hydrochloric acid (70mL×2), water (70 mL), saturated sodium bicarbonate (70 mL×2), 10% sodiumbisulfite solution (30 mL) and dried over magnesium sulfate.Purification was performed by flash chromatography on 800 g silica gel,loaded and eluted with 7% ethyl acetate in hexane. Pure, fractions werecombined and evaporated to give the title compound (4.1 g, 42%) as acolorless oil.

B. 3-Propylphenol

(1) 3-(1-Propenyl)phenol

To a suspension of (ethyl)triphenylphosphonium bromide (35 g, 94.3 mmol)in THF (95 mL) was added potassium bis(trimethylsilyl)amide (180 ml,0.5M in toluene, 90.2 mmol) dropwise. The reaction was stirred at 0° C.for 30 min, then a solution of 3-hydroxy-benzaldehyde (5 g, 41.0 mmol)in THF (5 mL) was added dropwise. After addition the reaction wasstirred at 0° C. for 1 h. Ethyl ether (200 mL) was added to dilute thereaction. The organic layer was washed with water (50 mL×2), brine (50mL×2) and dried over magnesium sulfate. Purification was performed byflash chromatography on 600 g silica gel, loaded and eluted with 10%ethyl acetate in hexane. Pure fractions were combined and evaporated togive the title compound (5.1 g, 93%) as a colorless oil.

(2) 3-Propylphenol

To a mixture of Part B (1) compound (3 g, 22.4 mmol) and 10% palladiumon carbon (150 mg) in THF (25 mL) was connected a hydrogen balloon.Hydrogenation was maintained at RT overnight. The mixture of reactionwas filtered through Celite. The resulting clear solution was evaporatedto give the title compound (2.97 g, 100%) as a yellowish oil.

C. 3-(3-Propylphenoxy)benzenepropanoic acid, ethyl ester

To a suspension of sodium hydride (155 mg, 6.44 mmol) in pyridine (25mL) was added a solution of Part B compound (1.5 g, 11.0 mmol) inpyridine (2.5 mL) at 0° C. under argon. Stirring was continued until thesolution was clear (15 min). The reaction was warmed to RT, and asolution of Part A compound (2.5 g, 8.27 mmol) in pyridine (2.5 mL) wasadded to the reaction followed by copper bromide-dimethyl sulfidecomplex (2.27 g, 11.0 mmol). The reaction was refluxed for 24 h. Thereaction was cooled to RT. The mixture of reaction was filtered andevaporated to dryness. Ethyl ether (250 mL) was added to the resultingresidue, and the organic layer was washed with 1N HCl (2×50 mL), water(2×50 mL), saturated sodium bicarbonate solution (50 mL), brine (50 mL)and dried over MgSO₄. Purification was performed by flash chromatographyon 200 g silica gel, loaded and eluted with 10% ethyl acetate in hexane.Pure fractions were combined and evaporated to give the title compound(1.68 g, 65%) as a colorless oil.

D. 3-(3-Propylphenoxy)benzenepropanol

Lithium aluminum hydride solution (5.29 mL, 1M in THF, 5.29 mmol) wasadded dropwise to a solution of Part C compound (1.65 g, 5.29 mmol) inTHF (10 mL) at 0° C. under argon. Stirring was continued for 10 min.Ethyl acetate (5 mL) was added to destroy excess LAH. Ethyl ether (200mL) was added and the organic layer was washed with 1N HCl solution(2×50 mL), H₂ O (50 mL), saturated sodium bicarbonate solution (50 mL),and brine (50 mL), then dried over MgSO₄. Evaporation gave the titlecompound (1.3 g, 91%) as a colorless oil.

E. 1-(3-Iodopropyl)-3-((3-propylphenoxy)benzene

A solution of iodine (1.35 g, 5.3 mmol) in THF (5 mL) was added to amixture of Part D compound (1.3 g, 1.43 mmol), triphenylphosphine (1.39g, 5.3 mmol) and imidazole (655 mg, 9.64 mmol) in THF (15 mL). Thereaction mixture was stirred at RT for 10 min, then diluted with hexane(200 ml). The organic layer was washed with 10% sodium bisulfite (50mL), saturated sodium bicarbonate (50 mL), brine (50 mL) and dried overMgSO₄. The solvent was evaporated to 100 mL volume, 6 g silica gel wasadded, and the mixture was evaporated to dryness. Flash chromatographywas performed on 200 g silica gel, loaded and eluted with hexane. Purefractions were combined and evaporated to give the title compound (1.6g, 88%) as a colorless oil.

F. α-(Diethoxyphosphinyl)benzenebutanesulfonic acid, cyclohexyl ester

To a stirred suspension of sodium hydride (126 mg, 5.26 mmol) in DMF (5mL) at 0° C. under argon, Example 1A Part B sulfonate (2.1 g, 6.58 mmol)in DMF (2 mL) was added dropwise over 15 min. The ice bath was removedand the reaction mixture was stirred am RT for 30 min. The reactionmixture was recooled to 0° C. and a solution of Part E compound (1.0 g,2.63 mmol) in DMF (2 mL) was added dropwise over 15 min. The mixture wasstirred at 0° C. for 2 h. The ice bath was removed and the reactionmixture was stirred at RT overnight. The mixture was diluted with ethylether (250 mL) and washed with H₂ O (50 ml), brine (50 mL) and driedover MgSO₄. Evaporation gave a crude oil. Purification was performed byflash chromatography on 150 g silica gel, loaded and eluted with 30%ethyl acetate in hexane. The pure fractions were combined and evaporatedto provide the title compound (1.1 g, 74%) as a colorless oil.

G. 3-(3-Propylphenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt

Ammonia gas was bubbled through a solution of Part F compound (800 mg,2.19 mmol) in methanol (10 mL) until the solution was saturated. Thesealed tube containing the reaction was heated at 70° C. overnight. Thereaction mixture was cooled to RT, evaporated to dryness and azeotropedwith toluene (2×20 mL). To a stirred solution of the resulting residuein dichloromethane (10 mL) at RT under argon was addedbromotrimethylsilane (2.22 mL, 15.3 mmol). The mixture was stirred at RTfor 20 h. The solvent was evaporated and the residue was pumped at highvacuum for 2 h. The residue was dissolved in 1M potassium hydroxide (8mL, 8 mmol) and the reaction mixture was stirred for 2 h. The resultingclear solution was purified by chromatography on CHP20P gel (2.5×20 cm),loaded and eluted with water followed by a gradient created by thegradual addition of CH₃ CN to a reservior of water. The combined purefractions, were concentrated to about 5 mL volume then lyophilized toprovide the title compound (500 mg, 42%) as a white solid.

IR (KBr) 2959, 2932, 1605, 1578, 1254, 1200, 1157, 1076, 966, 696 cm⁻¹

¹ H NMR (D₂ O, 400 MHz) δ7.21 (t, 2H, J=7.9 Hz) 6.99 (d, 1H, J=7.7 Hz)6.93 (d, 1H, J=7.7 Hz) 6.86 (s, 1H) 6.81 (s, 1H) 6.77 (d, 1H, J=10.3 Hz)6.74 (d, 1H, J=8.1) 2.77 (dt, 1H, J=6.0, 17.5 Hz) 2.51 (m, 2H) 2.44 (t,2H, J=7.5 Hz) 1.99-1.63 (m, 4H) 1.45 (m, 2H) 0.74 (t, 3H, J=7.5 Hz,)ppm.

¹³ C NMR (D₂ O, 100 MHz) δ156.99 156.95 145.96 145.80 130.28 129.97124.05 124.01 119.22 118.97 116.17 116.02 61.50 (d, J=118 Hz) 37.1635.40 31.22 28.55 23.98 13.02 ppm.

MS (FAB, + ions) m/z 505 (M-K+2H), 543 (M+H), 581 (M+K).

Anal. Calcd for C₁₉ H₂₂ K₃ O₇ PS 1.7 equiv H₂ O: C, 39.80; H, 4.47; P,5.40; S, 5.59. Found: C, 39.85; H, 3.43; P, 5.25; S, 5.68.

EXAMPLE 46

6-Methyl-α-phosphonobenzeneoctanesulfonic acid, tripotassium salt

A. ε-Methylbenzeneheptanol

A solution of 1.43 g (7.00 mmol) of Example 36 Part G alcohol((E)-5-methyl-7-phenyl-4-hepten-1-ol) in ethanol (100 mL) was stirredfor 0.5 h with 0.5 g of 10% Pd/C and filtered through a pad of celite.The filtrate was treated with 6.30 g (100 mmol) of ammonium formate and0.75 g of 10% Pd/C. The black suspension was stirred vigorouslyovernight and filtered through a pad of celite. The filtrate wasconcentrated leaving a colorless oil. The oil was diluted with ethylacetate, washed with solutions of NaHCO₃ and brine, dried (MgSO4) andconcentrated. The remainder was purified by flash chromatographyperformed on 150, g of silica gel eluted with 2:8 ethyl acetate/hexanesto provide 1.30 g (90%) of title alcohol as a colorless oil.

TLC Silica gel (3:7 ethyl acetate/hexanes) R_(f) =0.50.

IR (film) 3339, 3108, 3086, 3027, 2932, 2861, 1605, 1497, 1454, 1377,1055, 746 cm⁻¹.

¹ H NMR (CDCl₃, 400 MHz) δ7.25, 7.15 (two m, 5H) 3.55 (t, 2H, J=6.0 Hz)2.60 (m, 2H) 2.20 (s, 1H, O--H) 1.70-1.05 (m, 9H) 0.90 (d, 3H, J=6.3 Hz)ppm.

Mass Spec (CI--NH₃, + ions) m/e 224 (M+NH₄).

B. (7-Iodo-3-methylheptyl)benzene

To a stirred solution of 1.00 g (4.85 mmol) of Part A alcohol, 1.52 g(5.82 mmol) of triphenylphosphine, and 0.49 g (7.27 mmol) of imidazolein 30 mL of THF under argon at room temperature was added a solution of1.48 g (5.82 mmol) of iodine in 20 mL of THF, dropwise over 15 min.After the addition was complete, the reaction was diluted with 150 mL ofethyl acetate and washed with a saturated solution of Na₂ SO₃. Theorganic phase was dried (MgSO₄) and concentrated. The residue waspurified by flash chromatography on silica gel (100 g) eluted with 1 Lof hexanes to give 1.30 g (85%) of title iodide as a colorless oil.

TLC Silica gel (hexane) R_(f) =0.40

IR (film) 3027, 2928, 2857, 1603, 1495, 1454, 1429, 1375, 1217, 1171,1094, 1063, 1030 cm⁻¹.

¹ H NMR (CDCl₃, 270 MHz) δ7.25, 7.15 (two m, 5H) 3.15 (t, 2H, J=7.0 Hz)2.60 (m, 2H) 1.77 (quint, 2H, J=7.3 Hz) 1.60, 1.40, 1.15 (three m, 7H)0.90 (d, 2H, J=6.0 Hz) ppm.

Mass Spec (CI--NH₃, + ions) m/e 334 (M+NH₄), 316 (M).

C. α-(Diethoxyphosphinyl)-5-methylbenzeneoctanesulfonic acid, cyclohexylester

To a suspension of 112 mg (4.69 mmol) of NaH in 7 mL of dry DMF at 0° C.under argon was added 1.80 g (5.73 mmol) of Example 1A Part B sulfonateover 15 min. to give a yellow solution. The reaction was allowed to warmto room temperature and stir for 0.5 h when 1.10 g (3.48 mmol) of Part Biodide was added in one portion. The reaction mixture was stirred for 18h when it was quenched with saturated aq NH₄ Cl solution and dilutedwith ether. The organic fraction was washed with water, brine, dried(Na₂ SO₄) and evaporated to provide a crude yellow oil. Flashchromatography was performed on 150 g of silica gel eluted with 4:6ethyl acetate/hexane to provide 1.40 g (80%) of title compound as a paleyellow oil.

TLC Silica gel (4:6 ethyl acetate/hexane) R_(f) =0.28.

IR (CH₂ Cl₂, film) 3027, 2934, 2863, 1454, 1354, 1260, 1173, 1053, 1024,928, 866 cm⁻¹.

¹ H NMR (CDCl₃, 270 MHz) δ7.25, 7.15 (two m, 5H) 4.86 (m, 1H) 4.22 (m,4H) 3.45 (dt, 1H, J=19.5, 5.7 Hz) 2.60 (m 2H) 2.10 (m, 2H) 1.95 (m, 2H)1.67, 1.40 (two m, 17H) 1.35 (t, 6H, J=7.0 Hz) 0.90 (d, 3H, J=7.0 Hz)ppm.

Mass Spec (CI--NH₃, + ions) m/e 520 (M+NH₄), 503 (M+H), 438 (M+NH₄ -C₆H₁₀).

D. 6-Methyl-α-phosphonobenzeneoctanesulfonic acid, tripotassium salt

To a solution of 1.00 g (1.99 mmol) of Part C compound and 10 mL ofmethanol in a sealable tube at 0° C. was added 0.20 g (1.99 mmol) ofKHCO₃. The tube was sealed and placed in an oil bath at 70° C. for 36 h,at which point the tube was opened and the volatiles removed underreduced pressure. The remainder was dissolved in toluene and evaporatedtwo times (2×10 mL) leaving a colorless viscous oil. The oil wasdissolved in 7 mL of dry methylene chloride and treated with 0.80 mL(6.00 mmol) of bromotrimethylsilane. The reaction was allowed to stir atRT for 18 h when the solvent was evaporated and the residue pumped (≈0.5mm pressure) for 0.5 h. The remainder was dissolved by adding 4 mL (4mmol) of 1M KOH solution and stirring vigorously for ten min. The soapysolution was purified by MPLC on a column of CHP20P gel (250 mL) elutingwith water (150 mL) followed by a gradient created by the gradualaddition of 500 mL of acetonitrile to a reservoir of 300 mL of water.Approximately 7 mL fractions were collected. Fractions #26 to 31 werepooled, the acetonitrile was removed under reduced pressure and theaqueous solution lyophilized to provide 0.90 g (94%) of title compoundas a white lyophilate.

TLC Silica gel (6:3:1 n-propanol/conc. NH₃ /water) R_(f) =0.17.

IR (KBr) 3427, 3065, 3027, 2926, 2859, 1636, 1497, 1377, 1209, 1148,1084, 1044, 968, 698 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ7.25 (m, 4H) 7.10 (t, 1H, J=7.0 Hz) 2.77 (dt,1H, J=17.0, 5.6 Hz) 2.50 (m, 2H) 1.77 (m, 2H) 1.55-1.00 (m, 9H) 0.75 (d,3H, J=5.5 Hz) ppm.

Mass Spec (FAB, + ions) m/e 517 (M+K), 479 (M+H), 441 (M-K+2H).

Anal. Calc'd for C₁₅ H₂₂ O₆ SPK₃ +0.54 H₂ O: C, 36.89; H, 4.76; P, 6.34;S, 6.56 Found: C, 36.59; H, 5.10; P, 6.01; S, 6.83.

EXAMPLE 47

3-(2-Butylphenoxy)-α-phosphonobenzenepropanesulfonic acid, tripotassiumsalt

A. Tetrahydro-2-phenoxy-2H-pyran

Phenol (10 g, 106 mmol) was dissolved in 3,4-dihydro-2H-pyran (29 mL,318 mmol) and one drop concentrated HCl was added at RT. The reactionwas stirred at RT overnight. Ethyl ether (500 mL) was added to dilutethe reaction. The organic layer was washed with water (2×100 mL),saturated sodium bicarbonate (2×100 mL), brine (2×100 mL) and dried overMgSO₄. Evaporation gave title compound (17 g, 100%) as a colorless oil.

B. 2-(2-Butytphenoxy)tetrahydro-2H-pyran

To a solution of Part A compound (5 g, 31.3 mmol) in THF (69 mL) andethyl ether (37 mL) was added dropwise a solution of 2.5M n-butyllithiumin hexane (15.5 mL, 38.8 mmol) at 0° C. over 10 min. After an additional30 min at 0° C., the reaction was allowed to warm to RT for 5 h. Thereaction was recooled to 0° C. and iodobutane (7.55 mL, 66.4 mmol) wasadded. After 10 min at 0° C., the reaction was allowed to warm to RT andstirring was continued overnight. Ethyl ether (300 mL) was added todilute the reaction, and the organic layer was washed with 1N HCl (2×50mL), saturated sodium bicarbonate (2×50 mL), brine (2×50 mL) and driedover MgSO₄. Evaporation gave title compound (6.0 g, 89%) as a crude oil.

C. 2-Butylphenol

To a solution of Part B compound (6.0 g, 27.8 mmol) in dioxane (250 mL)was added 10% HCl solution (100 mL) at RT. The reaction was stirred atRT for 3.5 h. Ethyl ether (200 mL) was added to dilute the reaction. Theorganic layer was washed with saturated sodium bicarbonate solution(2×100 mL), brine (2×100 mL) and dried over MgSO₄. Purification wasperformed by flash chromatography on silica gel (500 g), loaded andeluted with 10% ethyl acetate in hexane. Pure fractions was combined andevaporated to give title compound (3.0 g, 70%) as a colorless oil.

D. 3-(2-Butylphenoxy)benzenepropanoic acid, ethyl ester

To a suspension of potassium hydride (572 mg, 14.3 mmol) [obtained bywashing a 35 wt.% suspension of KH in mineral oil with hexane severaltimes followed by evaporation of excess hexane] in pyridine (20 mL) wasadded a solution of Part C compound (2.2 g, 14.3 mmol) in pyridine (2.5mL) at 0° C. under argon. Stirring was continued until the solution wasclear (15 min). The reaction was warmed to RT, and a solution of Example45 Part A iodide (2.9 g, 9.53 mmol) in pyridine (2.5 mL) was added tothe reaction followed by copper bromidedimthyl sulfide complex (2.94 g,14.3 mmol). The reaction was refluxed for 16 h. Ethyl ether (150 mL) wasadded to dilute the reaction. The resulting mixture was filtered throughCelite, the filtrate was evaporated to dryness. Ethyl ether (200 mL) wasadded and the organic layer was washed with 1N HCl (2×50 mL), water(2×50 mL), 1N potassium hydroxide solution (2×50 mL), brine (50 mL) anddried over MgSO₄. Purification was performed by flash chromatography on200 g silica gel, loaded and eluted with 7% ethyl acetate in hexane.Pure fractions were combined and evaporated to give title compound (1.2g, 38%) as a colorless oil.

E. 3-(2-Butylphenoxy)benzenepropanol

Lithium aluminum hydride (LAH) solution (2.52 mL, 1M in THF, 2.52 mmol)was added dropwise to a solution of Part D compound (820 mg, 2.52 mmol)in THF (8 mL) at 0° C. under argon. Stirring was continued for 10 min.Methanol (5 mL) was added to destroy excess LAH. Ethyl ether (150 mL)was added and the organic layer was washed with 1N HCl solution (2×50mL), H₂ O (50 mL), saturated sodium bicarbonate solution (50 mL), andbrine (50 mL), then dried over MgSO₄. Evaporation gave title compound(620 mg, 87%) as a colorless oil.

F. 1-(2-Butylphenoxy)-3-(3-iodopropyl)benzene

A solution of iodine (589 mg, 2.32 mmol) in THF (2 mL) was added to amixture of Part E alcohol (600 mg, 2.11 mmol), triphenylphosphine (607mg, 2.32 mmol) and imidazole (287 mg, 4.22 mmol) in THF (10 mL). Thereaction mixture was stirred at RT for 10 min, then diluted with hexane(150 ml). The organic layer was washed with 10% sodium bisulfite (50mL), saturated sodium bicarbonate (50 mL), brine (50 mL) and dried overMgSO₄. The solvent was evaporated to 100 ml volume, 5 g silica gel wasadded, and the mixture was evaporated to dryness. Flash chromatographywas performed on 100 g silica gel, loaded and eluted with hexane. Purefractions were combined and evaporated to give title compound (720 mg,87%) as a colorless oil.

G. 3-(2-Butylphenoxy)-α-(diethoxyphosphinyl) benzenebutanesulfonic acid,cyclohexyl ester

To a stirred suspension of sodium hydride (45.2 mg, 1.89 mmol) in DMF (2mL) at 0° C. under argon, Example 1A Part B sulfonate (642 mg, 2.04mmol) in DMF (2 mL) was added dropwise over 15 min. The ice bath wasremoved and the reaction mixture was stirred at RT for 30 min. Thereaction mixture was recooled to 0° C. and a solution of Part F compound(620 mg, 1.57 mmol) in DMF (2 mL) was added dropwise over 15 min. Themixture was stirred at 0° C. for 2 h. The ice bath was removed and thereaction mixture was stirred at RT overnight. The mixture was dilutedwith ethyl ether (150 mL) and washed with H₂ O (50 mL), brine (50 mL)and dried over MgSO₄. Evaporation gave a crude oil. Purification wasperformed by flash chromatography on 150 g silica gel, loaded and elutedwith 25% ethyl acetate in hexane. The pure fractions were combined andevaporated to provide title compound (650 mg, 71%) as a colorless oil.

H. 3-(2-Butylphenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt

Ammonia gas was bubbled through a solution of Part G compound (650 mg,1.12 mmol) in methanol (10 mL) until the solution was saturated. Thesealed tube was heated at 70° C. overnight. The reaction mixture wascooled to RT, evaporated to dryness and azeotroped with toluene (2×20mL). To a stirred solution of the resulting residue in dichloromethane(10 mL) at RT under argon was added bromotrimethylsilane (1.10 mL, 7.84mmol). The mixture was stirred at RT for 20 h. The solvent wasevaporated and the residue was pumped at high vacuum for 2 h. Theresidue was dissolved in 1M potassium hydroxide (8 mL, 8 mmol) and thereaction mixture was stirred for 2 h. The solution was lyophilized togive a white solid. The crude product was purified by chromatography onCHP20P gel (2.5×20 cm), loaded and eluted with water and followed by agradient created by the gradual addition of CH₃ CN to a reservior ofwater. The combined pure fractions were concentrated to about 5 mLvolume then lyophilized to provide title compound (350 mg, 56%) as awhite solid.

IR (KBr) 2957, 2932, 1613, 1578, 1485, 1248, 1219, 1072, 964, 557 cm⁻¹.

¹ H NMR (D₂ O, 400 MHz) δ7.26 (d, 1H, J=6.4 Hz) 7.16 (t, 1H, J=8.4 Hz)7.14 (t, 1H, J=8.5 Hz) 7.08 (t, 1H, J=6.8 Hz) 6.92 (d, 1H, J=7.3 Hz)6.87 (d, 1H, J=8.2 Hz) 6.73 (s, 1H) 6.64 (d, 1H, J=8.2 Hz) 2.78 (dt, 1H,J=6.0, 17.6 Hz) 2.45 (2t, 4H, J=7.7 Hz) 1.99-1.61 (m, 4H) 1.40 (pentet,2H, J=7.7 Hz) 1.13 (sextet, 2H, J=7.3 Hz) 0.69 (t, 3H, J=7.7 Hz) ppm.

¹³ C NMR (D₂ O, 100 MHz) δ158.14 153.62 145.77 135.35 131.10 129.92127.60 124.92 123.00 120.82 117.06 114.24 61.58 (d, J=120 Hz) 35.4931.92 31.37 29.15 28.68 21.88 13.23 ppm.

MS (FAB, + ions) m/z 557 (M+H), 595 (M+K).

Anal. Calc'd for C₂₀ H₂₄ K₃ O₇ PS+1.8 equiv H₂ O: C, 40.77; H, 4.72; P,5.26; S, 5.44. Found: C, 40.84; H, 4.87; P, 5.10; S, 5.38.

EXAMPLE 48

(E,E)-1-Fluoro-6,10,14-trimethyl-1-phosphono-5,9,13-pentadecatriene-1-sulfonicacid, tripotassium salt

A.(E,E)-1-(Diethoxyphosphinyl)-1-fluoro-5,9,13-pentadecatriene-1-sulfonicacid, cyclohexyl ester

To a suspension of 81 mg (2.0, mmol, 1.1 eq) of sodium hydride (as a 60%mineral oil dispersion) in 1 mL of THF at 0° C. was added a solution of1.0 g (1.8 mmol, 1 eq) of Example 1A Part C compound in 3 mL of THF. Thebubbling solution was warmed to RT and stirred for 30 min, then cooledto -78° C. A solution of 721 mg (2.3 mmol, 1.25 eq) ofN-fluorobenzenesulfonimide in 2 mL of THF was added over 2 min and thereaction was stirred at -78° C. for 1 h, then warmed to RT and stirredfor 2 h. The reaction was quenched by the addition of saturated ammoniumchloride, then diluted with ether. The aqueous layer was extracted withether and the combined organic solutions were stirred with 10% sodiumthiosulfate for 30 min. The organic layer was washed with 10% KOH, driedand concentrated. Flash chromatography of the crude product on silicagel (75 g) eluding with 25% ethyl acetate in hexane afforded 674 mg(65%) of title compound as a clear colorless oil.

TLC Silica gel (10% ether in CH₂ Cl₂) R_(f) =0.78.

B.(E,E)-1-Fluoro-6,10,14-trimethyl-1-phosphono-5,9,13-pentadecatriene-1-sulfonicacid, tripotassium salt

To a solution of 660 mg (1.2 mmol, 1 eq) of Part A compound in 10 mL ofmethanol at 0° C. in a thick-walled, sealable tube was bubbled ammoniauntil the solution was saturated. The reaction tube was then sealed andheated am 75° C. for 19 h. The reaction mixture was allowed to cool toRT and concentrated. The oily residue was coevaporated once withtoluene, then with 10% hexamethyldisilazane in toluene (2×10 mL) toafford a clear oil.

To a solution of the oil in 5 mL of dry CH₂ Cl₂ at RT was added 986 μL(4.7 mmol, 4 eq) of hexamethyldisilazane followed by 771 μL (5.8 mmol, 5eq) of bromotrimethylsilane (TMSBr) dropwise over 1 min. After 22 h atRT, the reaction was concentrated and the resulting semisolid was placedon high vacuum (0.25 mm Hg) for 1 h. The residue was dissolved by adding4.7 mL (4 eq) of 1M potassium hydroxide followed by 5 mL of water,frozen and lyophilized to afford an off-white lyophilate. The lyophilatewas purified by MPLC on a column of CHP20P (2.5 cm×25 cm) elutinginitially with 150 mL of water followed by a gradient formed by gradualaddition of 400 mL of 50% acetonitriie in water to a reservoircontaining 400 mL of water. Fractions containing pure product werepooled, concentrated, filtered, frozen and lyophilized. The lyophilatewas dissolved in a minimum amount of water and concentrated. Theresulting semisolid residue was triturated with acetone to afford, afterhigh vacuum (0.025 mm Hg) removal of acetone remnants, 236 mg (60%) of awhite solid.

TLC silica gel (5:4:1 n-Propanol:ammonium hydroxide:water): R_(f) =0.43.

IR (KBr): 3426(br), 2969, 2926, 2857, 1663, 1451, 1213, 1101, 982 cm⁻¹.

¹ H NMR (D₂ O, 300 MHz): δ5.14 (t, J=7 Hz, 1H) 5.06 (t, J=7 Hz,1H) 5.04(t, J=7 Hz, 1H) 2.07 (m, 2H) 1.90 (m, 10H) 1.54 (s, 3H) 1.50 (m, 2H)1.49 (s, 3H) 1.46 (s, 6H) ppm.

¹³ C NMR (D₂ O, 75.6 MHz): δ136.4 135.9 132.6 125.0 124.7 124.6 107.9(dd, J_(CF) =211 Hz, J_(cp) =140 Hz) 39.4 39.3 34.0 (d, J_(CF) =211 Hz)28.4 26.4 26.2 25.2 23.7 (t, J_(CP) =J_(CF) =3 Hz) 17.3 15.6 15.5 ppm.

¹⁹ F NMR (D₂ O, 282.8 MHz): δ165.1 (ddd, J_(PF) =66 Hz, J_(HF) =23, 20Hz) ppm.

³¹ P NMR (D₂ O, 121.7 MHz): δ8.5 (d, J_(FP) =66 Hz) ppm.

Mass Spec (FAB, + ions): m/z 541 (M+H), 503 (M+2H-K).

Anal. Calcd for C₁₈ H₂₉ O₆ FPSK₃ +1.13 H₂ O: C, 38.53; H, 5.62; S, 5.71;P, 5.52 Found: C, 38.53; H, 5.87; S, 5.40; P, 5.38.

EXAMPLE 49

(E,E)-1-[Bis[1-(1-Oxopropoxy)ethoxy]phosphinyl]-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, monopotassium salt

A. Propanoic acid, 1-chloroethyl ester

To freshly fused zinc chloride (50 mg) was added CH₂ Cl₂ (20 mL)followed by propionyl chloride (10.0 g, 108 mmol). The mixture wascooled to 10° C. and acetaldehyde (6.0 mL, 108 mmol) was added over 5min. The brown reaction was allowed to warm to RT, then stirred at thattemperature overnight. The reaction was diluted with CH₂ Cl₂ (50 mL) andwashed with 20% aqueous sodium acetate (20 mL). The organic layer wasdried over MgSO₄ and evaporated to give a brown oil, which was distilledunder high vacuum (0.5 torr) to give title compound (1.48 g, 10%) in theform of a clear, colorless liquid. bp 28°-31° C.

B.(E,E)-1-[Bis[1-(1-Oxopropoxy)ethoxy]phosphinyl]-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, monopotassium salt

A solution of Example 1B tripotassium salt (500 mg, 0.953 mmol) in water(3 mL) was added dropwise slowly via syringe pump at a rate of 0.24mL/min to a solution of silver nitrate (586 mg, 3.44 mmol) in water (2mL) at RT under argon. A white precipitate began to form immediatelyupon addition. The reaction was stirred at RT for 10 min, then filtered.The solid obtained was washed with water (2×2 mL) and diethyl ether (2mL), then pumped under high vacuum for 7 h to give 567 mg of a silversalt in the form of a white solid.

To a suspension of the silver salt prepared above in CH₂ Cl₂ (2 mL)under argon in the dark at RT was added 2,4,6-collidine (110 μL, 0.836mmol) followed by a solution of Part A compound (568 mg, 4.18 mmol) inCH₂ Cl₂ (1 mL). The reaction was stirred at RT for 6 h, filtered throughCelite with the aid of CH₂ Cl₂, then concentrated in vacuo to give anopaque oil. The crude material was dissolved in EtOAc (10 mL) and washedwith 1N HCl (5×2 mL), saturated KHCO₃ (2×2 mL), and saturated KCl (2mL), then dried over anhydrous KCl. Evaporation gave a pale yellow oil,which was chromatographed (2.5×20 cm CHP20P gel, 10 mL fractions, waterelution followed by a gradient of acetonitrile in water). Theproduct-containing fractions were combined and evaporated to give anopaque gum, which was dissolved in CH₂ Cl₂ and dried over anhydrous KCl.Evaporation gave title compound (369 mg, 68%) as a colorless oil as amixture of four diastereomers.

TLC (silica gel) (15:85 MeOH/CH₂ Cl₂): R_(f) =0.42.

IR (neat) 2940, 2924, 1751, 1256, 1209, 1107, 1084, 1047, 978, 949 cm⁻¹.

¹ H NMR (DMSO, 400 MHz) δ6.53 (m, 2H) 5.09 (m, 3H) 3.07-2.85 (m, 1H)2.32 (m, 4H) 2.09-1.65 (m, 12H) 1.63 (s, 3H) 1.62-1.43 (m, 2H) 1.56 (s,9H) 1.42 (m, 6H) 1.03 (m, 6H) ppm.

Mass Spec (FAB, + ions) m/z 685 (M+K).

Anal. Calcd for C₂₈ H₄₈ KO₁₀ PS: C, 51.99; H, 7.48; P, 4.79; S, 4.96.Found: C, 51.69; H, 7.49; P, 4.44; S, 5.92.

The following additional examples may be prepared employing proceduressee out hereinbefore including in the working Examples.

50. (E)-6-methyl-10-phenyl-1-phosphono-5-decene-1-sulfonic acid,tripotassium salt;

Mas Spec (FAB, + ions) m/z 519 (M+H), 481 (M+2H-K).

Anal. Calcd for C₁₈ H₂₆ O₆ SPK₃ +1.3 H₂ O: C, 39.82; H, 5.33; P, 5.70;S, 5.90 Found: C, 39.82; H, 5.63; P, 5.49; S, 5.65.

51. (E)-9-cyclopentyl-6-methyl-1-phosphono-5-nonene-1-sulfonic acid,tripotassium salt;

Mass Spec (Ion Spray, + ions) m/z 445 (M-K+2H), 483 (M+H).

Anal. Calcd for C₁₅ H₂₆ O₆ SPK₃ +0.70 H₂ O: C, 36.39; H, 5.57; P, 6.26;S, 6.48 Found: C, 36.60; H, 5.98; P, 5.92; S, 6.23.

52. α-phosphono-4α-methyl[1,1'-biphenyl]-4-butanesulfonic acid,tripotassium salt;

Mass Spec (electrospray, CH₃ CN, NH₃, + ions) m/z 508 (M-3K+4H+3CH₃ CN),467 (M-3K+4H+2CH₃ CN), 461 (M-K+2H), 443 (M-3K+3H+NH₄ +CH₃ CN), 426(M-3K+4H+CH₃ CN), 423 (M+H-2K), 402 (M-3K+3H+NH₄), 385 (M-3K+4H).

Anal. Calcd for C₁₇ H₁₈ K₃ O₆ PS+1.4 H₂ O: C, 38.98; H, 4.00; P, 5.91;S, 6.12 Found: C, 39.32; H, 4.03; P, 6.12; S, 5.73.

53. α-phosphono-4-(3-propylphenoxy)benzene-butanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 429 (M+4H-3K), 467 (M+3H-2K), 505 (M+2H-K),543 (M+H).

Anal. Calcd for C₁₉ H₂₂ K₃ O₇ PS+0.5 H₂ O: C, 41.36; H, 4.20; P, 5.61;S, 5.81 Found: C, 41.17; H, 3.96; P, 5.40; S, 5.98.

54. 4'-ethyl-α-phosphono[1,1'-biphenyl]-4-butanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 551 (M+K), 513 (M+H), 475 (M-K+2H).

Anal. Calcd for C₁₈ H₂₀ K₃ O₆ PS+1.2 H₂ O: C, 40.48; H, 4.22; P, 5.80;S, 6.00 Found: C, 40.17; H, 4.32; P, 5.97; S, 6.45.

55. 4'-chloro-α-phosphono[1,1'-biphenyl]-4-butanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 557/9 (M+K), 519/21 (M+H), 481/3 (M-K+2H).

Anal. Calcd for C₁₆ H₁₅ ClK₃ O₆ PS+0.75 H₂ O: C, 36.10; H, 3.12; Cl,6.66; P, 5.82; S, 6.02 Found: C, 35.88; H, 3.02; Cl, 6.88; P, 5.62; S,6.42.

56. 14-methyl-1-phosphono-13-pentadecene-1-sulfonic acid, tripotassiumsalt;

Mass Spec (FAB, + ions) m/z 537 (M+K), 499 (M+H), 461 (M-K+2H).

Anal. Calcd for C₁₆ H₃₀ O₆ SPK₃ +2.3 H₂ O: C, 35.63; H, 6.45; P, 5.74;S, 5.94 Found: C, 35.63; H, 6.27; P, 5.71; S, 6.14.

57. 4-(phenylthio)-α-phosphonobenzenebutane-sulfonic acid, tripotassiumsalt;

Mass Spec (FAB, + ions) m/z 441 (M+3H-2K), 479 (M+2H-K), 517 (M+H).

Anal. Calcd for C₁₆ H₁₆ K₃ O₆ PS₂ +1.6 H₂ O: C, 35.23; H, 3.55; P, 5.68;S, 11.76 Found: C, 34.89; H, 3.79; P, 5.46; S, 12.19.

58. α-phosphono-4-propylbenzeneoctanesulfonic acid, tripotassium salt;

Mass Spec (electrospray, + ions) m/z 427 [(M+3H-3K)+NH₃ +NH₄ ], 448[(M+2H-2K)+NH₄ ], 469 (M+2H-K).

Anal. Calcd for C₁₇ H₂₆ K₃ O₆ PS+1.0 H₂ O: C, 38.91; H, 5.38; P, 5.90;S, 6.11 Found: C, 39.22; H, 5.27; P, 5.50; S, 6.14.

59. α-phosphono-3-(4-propylphenoxy)benzene-butanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 505 (M-K+2H), 543 (M+H), 581 (M+K).

Anal. Calcd for C₁₉ H₂₂ K₃ O₇ PS+1.4 H₂ O: C, 40.18; H, 4.40; P, 5.45;S, 5.65 Found: C, 40.16; H, 4.72; P, 5.42; S, 6.06.

60. 4-[3-(2-methyl-1-propenyl)phenoxy]-α-phosphonobenzenebutanesulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 517 (M-K+2H), 555 (M+H), 593 (M+K).

Anal. Calcd for C₂₀ H₂₂ K₃ O₇ PS+1.0 H₂ O: C, 41.94; H, 4.22; P, 5.42;S, 5.60 Found: C, 42.01; H, 4.10; P, 5.53; S, 5.57.

61. (10S)-10,14-dimethyl-1-phosphono-13-pentadecene-1-sulfonic acid,dipotassium salt;

Mass Spec (FAB, + ions) m/z 513 (M+H), 457 (M+2H-K), 437 (M+3H-2K).

Anal. Calcd for C₁₇ H₃₃ O₆ PSK₂ +2.0 H₂ O: C, 39.98; H, 7.30; P, 6.06;S, 6.28 Found: C, 39.92; H, 6.99; P, 5.89; S, 6.27.

62.(E,E)-1-phosphono-3-[(3,7,11-trimethyl-2,6,10-dodecatrienyl)oxy]-1-propanesulfonicacid, tripotassium salt;

Mass Spec (FAB), + ions) m/z 577 (M+K), 539 (M+H).

Anal. Calcd for C₁₈ H₃₀ O₇ PSK₃ +1.25 H₂ O: C, 38.51; H, 5.84; P, 5.52;S, 5.94 Found: C, 38.51; H. 5.95; P, 5.18; S, 5.52.

63.(E,E)-6,10,14-trimethyl-1-phosphono-5,9,13-pentadecatriene-1-sulfonicacid, 4-(methylthio)phenyl ester, dipotassium salt:

Mass Spec (FAB, + ions) m/z 645 (M+K), 607 (M+H).

Anal. Calcd for C₂₅ H₃₇ O₆ PS₂ K₂ +4.6 H₂ O: C, 43.53; H, 6.75; P, 4.49;S, 9.30 Found: C, 43.16; H, 6.25; P, 4.26; S, 9.53.

64. 4-(3-methylphenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 515 (M+H), 553 (M+K).

Anal. Calcd for C₁₇ H₁₈ K₃ O₇ PS+2.1 H₂ O: C, 36.96; H, 4.05: P, 5.61:S, 5.80 Found: C, 36.94; H, 4.40; P, 5.49: S, 5.94.

65.(E,E)-1-[bis[[(cyclohexylacetyl)oxy]methoxy]phosphinyl]-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, monopotassium salt;

Mass Spec (FAB, + ions) m/z 793 (M+K).

Anal. Calcd for C₃₆ H₆₀ KO₁₀ PS: C, 57.27; H, 8.01; P, 4.10; S, 4.25Found: C, 57.06; H, 8.03; P, 4.01; s, 4.56.

66.(E,E)-1-[bis[(benzoyloxy)methoxy]phosphinyl]-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, monopotassium salt;

Mass. Spec (FAB, + ions) m/z 753 (M+K).

Anal. Calcd for C₃₄ H₄₄ PSO₁₀ K+0.53 H₂ O: C, 56.37; H, 6.27; P, 4.28;S, 4.43 Found: C, 56.37; H, 6.32; P, 4.37; S, 4.32.

67. 4-(benzoylphenylamino)-α-phosphonobenzene-butanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 642 (M+K), 604 (M+H), 566 (M-K+2H).

Anal. Calcd for C₂₃ H₂₁ NO₇ SPK₃ +4.0 H₂ O: C, 40.88; H, 4.33; N, 2.07;P, 4.58; S, 4.74 Found: C, 40.71; H, 4.28; N, 2.12; P, 4.76; S, 4.87.

68. 3-(benzoylphenylamino)-α-phosphonobenzene-butanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 642 (M+K), 604 (M+H), 566 (M-K+2H).

Anal. Calcd for C₂₃ H₂₁ NO₇ SPK₃ +2.50 H₂ O: C, 42.58; H, 4.04; N, 2.16;P, 4.77; S, 4.94 Found: C, 42.73; H, 4.24; N, 2.47; P, 4.56; S, 4.88.

69. 4-(phenylamino)-α-phosphonobenzenebutanesulfonic acid, tripotassiumsalt;

Mass Spec (FAB, + ions) m/z 538 (M+K), 500 (M+H), 462 (M-K+2H).

Anal. Calcd for C₁₆ H₁₇ NO₆ SPK₃ +2.0 H₂ O: C, 35.87; H, 3.95; N, 2.61;P, 5.78 Found: C, 36.08; H, 3.96; N, 2.47; P, 5.61.

70. 3-(phenylamino)-α-phosphonobenzenebunane-sulfonic acid, tripotassiumsalt;

Mass spec (FAB, + ions) m/z 538 (M+K), 500 (M+H), 462 (M-K+2H).

Anal. Calcd for C₁₆ H₁₇ NO₆ SPK₃ +1.0 H₂ O: C, 37.12; H, 3.70; N, 2.71;P, 5.98; S, 6.19 Found: C, 36.97; H, 3.99; N, 2.47; P, 5.98; S, 6.14

71. 4-(phenylsulfinyl)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 457 (M-2K+3H), 495 (M-K+2H), 533 (M+H).

Anal. Calcd for C₁₆ H₁₆ K₃ O₇ PS₂ +1.2 H₂ O: C, 34.67; H, 3.35; P, 5.59;S, 11.57 Found: C, 34.68; H, 3.23; P, 5.27; S, 11.41

72. 4-(2-methylphenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 477 (M-K+2H), 515 (M+H), 553 (M+K).

Anal. Calcd for C₁₇ H₁₈ K₃ O₇ PS+2.3 H₂ O: C, 36.72; H, 4.10; P, 5.57;S, 5.77 Found: C, 36.72; H, 3.91; P, 5.51; S, 5.54

73.4-phenoxy-α-phosphonobenzenepentanesulfonic acid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 476 (M-K+2H), 515 (M+H), 553 (M+K)

Anal. Calcd for C₁₇ H₁₈ K₃ O₇ PS+1.3 H₂ O: C, 37.95; H, 3.86; P, 5.76;S, 5.96 Found: C, 38.15; H, 4.26; P, 5.63; S, 6.48

74. 4-(2-Fluorophenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 481 (M-K+2H), 519 (M+H), 557 (M+K).

Anal. Calcd for C₁₆ H₁₅ FK₃ O₇ PS+2.6 H₂ O: C, 33.99; H, 3.60; P, 5.48;S, 5.67 Found: C, 34.14; H, 3.34; P, 5.53; S, 5.27

75. 4-(2-methoxyphenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 493 (M-K+2H), 531 (M+H), 569 (M+K).

Anal. Calcd for C₁₇ H₁₈ K₃ O₈ PS+2.6 H₂ O: C, 35.36; H, 4.05; P, 5.36:S, 5.55 Found: C, 35.37; H, 3.81; P, 5.46; S, 5.47

76.(E,E)-1-[bis[[(1-oxoheptyl)oxy]methoxy]-phosphinyl]-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, monopotassium salt;

Mass Spec (FAB, + ions) m/z 769 (M+K), 731 (M+H).

Anal. Calcd for C₃₄ H₆₀ PSO₁₀ K+0.06 H₂ O: C, 55.79; H, 8.28; P, 4.23;S, 4.38 Found: C, 55.79; H, 8.38; P, 4.31; S, 4.00

77. 4-[(4-bromophenyl)thio]-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec HRMS (FAB, + ions) calcd for C₁₆ H₁₇ ⁷⁹ BrK₂ O₆ PS₂ : 556.8662(M-K+2H) Found: 556.8691

Anal. Calcd for C₁₆ H₁₅ BrK₃ O₆ PS₂ +1.8 H₂ O: C, 30.60; H, 2.99; P,4.93; S, 10.21 Found: C, 30.89; H, 3.06; P, 4.54; S, 10.16

78. 4-(phenylsulfonyl)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 473 (M-2K+3H), 511 (M-K+2H), 549 (M+H), 587(M+K).

Anal. Calcd for C₁₆ H₁₆ K₃ O₈ PS₂ +2.6 H₂ O: C, 32.27; H, 3.59; P, 5.20;S, 10.77 Found: C, 32.63; H, 3.54; P, 4,80; S, 9.55

79. 4-phenoxy-α-phosphonobenzenepropanesulfonic acid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 449 (M-K+2H), 487 (M+H), 525 (M+K).

Anal. Calcd for C₁₅ H₁₄ K₃ O₇ PS+1.3 H₂ O: C, 35.34; H, 3.28; P, 6.08;S, 6.29 Found: C, 35.34; H, 3.49; P, 5.92; S, 6.48

80. 6-methyl-9-phenyl-α-phosphono-5-nonene-1-sulfonic acid, tripotassiumsalt;

Mass Spec (FAB, + ions) m/z 529 (M+K), 491 (M+H).

Anal. Calcd for C₁₆ H₂₂ PSO₆ K₃ +3.6 H₂ O: C, 34,62; H, 5.29; P, 5.58;S, 5.78 Found: C, 34.29; H, 5.01; P, 5.60; S, 5.74

81.(E,E)-1-[bis[(2-methyl-1-oxopropoxy)methoxy]phosphinyl]-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, monopotassium salt;

Mass Spec (FAB, + ions) m/z 685 (M+K).

Anal. Calcd for C₂₈ H₄₈ PSO₁₀ K+1.0 H₂ O: C, 50.54; H, 7.58; P, 4.51; S,4.82 Found: C, 50.54; H, 7.47; P, 4.51; S, 4.85

82. 4-(2-butylphenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 519(M-K+2H), 557 (M+H), 595 (M+K).

Anal. Calcd for C₂₀ H₂₄ K₃ O₇ PS+1.3 H₂ O: C, 41.36; H, 4.63; P, 5.33;S, 5.52 Found: C, 41.36; H, 4.98; P, 5.04; S, 5.54

83. (E)-6-methyl-7-(4-methylphenoxy)-1-phosphono-5-heptene-1-sulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 531 (M+K), 493 (M+H), 455 (M-K+2H).

Anal. Calcd for C₁₅ H₂₀ O₇ PSK₃ +2.1 H₂ O: C, 33.96; H, 4.60; P, 5.84;S, 6.04 Found: C, 34.34; H, 5.00; P, 6.11; S, 5.81

84. (E)-6-methyl-8-(4-methylphenyl)-1-phosphono-5-octenyl-1-sulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 529 (M+K), 491 (M+H), 453 (M-K+2H).

Anal. Calcd for C₁₆ H₂₂ O₆ PSK₃ +1.74 H₂ O: C, 36.82; H, 4.92; P, 5.93;S, 6.14 Found: C, 36.82; H, 5.35; P, 5.98; S, 6.11

85. (E)-6-methyl-7-(3-methylphenoxy)-1-phosphono-5-heptene-1-sulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) 531 (M+K), 493 (M+H), 455 (M-K+2H).

Anal. Calcd for C₁₅ H₂₀ O₇ PSK₃ +0.85 H₂ O: C, 35.47; H, 4.30; P, 6.10;S, 6.31 Found: C, 35.91; H, 4.73; P, 6.34; S, 6.42

86. 4-(1-naphthalenyl)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 535 (M+H), 497 (M-K+2H), 459 (M-2K+3H).

Anal. Calcd for C₂₀ H₁₈ K₃ O₆ PS+2.24 H₂ O: C, 41.77; H, 3.94; S, 5.58;P, 5.39 Found: C, 42.17; H, 4.38; S, 5.24; P, 5.50

87. 4-(2,6-dimethylphenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt; Mass Spec (FAB, + ions) m/z 491 (M-K+2H), 529 (M+H),567 (M+K).

Anal. Calcd for C₁₈ H₂₀ K₃ O₇ PS+2.9 H₂ O: C, 37.17; H, 4.48; P, 5.32;S, 5.51 Found: C, 37.17; H, 4.44; P, 5.12; S, 5.91

88. 3-(3-methylphenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 553 (M+K), 515 (M+H).

Anal. Calcd for C₁₇ H₁₈ K₃ O₇ PS+1.5 H₂ O: C, 37.69; H, 3.91: P, 5.72;S, 5.92 Found: C, 37.74; H, 3.92; P, 5.78; S, 6.24

89. (E)-6,10-dimethyl-1-phosphono-5,9-pentadecadiene-1-sulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 549 (M+K), 511 (M+H), 473 (M+2H-K).

Anal. Calcd for C₁₇ H₃₀ O₆ PSK₃ +0.35 H₂ O: C, 39.49; H, 5.98; P, 5.99;S, 6.20 Found: C, 39.51; H, 6.16; P, 5.17; S, 5.98

90. 4-(2-benzofuranyl)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec m/z (FAB, + ions) 525 (M+H), 487 (M-K+2H), 449 (M-2K+3H).

Anal. Calcd for C₁₈ H₁₆ K₃ PO₇ PS+4.5 H₂ O: C, 35.66; H, 4.17; P, 5.11;S, 5.29 Found: C, 35.66; H, 4.18; P, 4.83; S, 4.95

91. α-phosphono-4'-propyl[1,1'-biphenyl]-4-pentanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 541 (M+H), 503 (M+2H-K), 465 (M+3H-2K).

Anal. Calcd for C₂₀ H₂₄ O₆ PSK₃ +1.26 H₂ O: C, 42.64; H, 4.47; P, 5.50;S, 5.69 Found: C, 42.64; H, 5.11; P, 5.20; S, 5.90

92. 3-(2-methylphenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 515 (M+H), 553 (M+K)

Anal. Calcd for C₁₇ H₁₈ K₃ O₇ PS+1.7 H₂ O: C, 37.45; H, 3.96; P, 5.68;S, 5.88 Found: C, 37.49; H, 4.07; P, 5.66; S, 6.00

93.α-[bis[(2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]-3-phenoxybenzenebutanesulfonicacid, monopotassium salt;

Mass Spec (FAB, + ions) m/z 653 (M+H), 691 (M+K).

Anal. Calcd for C₂₈ H₃₈ KO₁₀ PS: C, 51.52; H, 5.87; P, 4.75; S, 4.91Found: C, 51.33; H, 5.62; P, 4.54; S, 4.75

94. 11-Phenyl-1-phosphono-1-undecanesulfonic acid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 545 (M+K), 507 (M+H), 469 (M+2H-K).

Anal. Calcd for C₁₇ H₂₆ K₃ O₆ PS+0.5 H₂ O: C, 39.59; H, 5.28; P, 6.01;S, 6.22 Found: C, 39.61; H, 5.44; P, 5.77; S, 6.46

95. α-phosphonobenzeneoctanesulfonic acid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 503 (M+K), 465 (M+H).

Anal. Calcd for C₁₄ H₂₀ K₃ O₆ PS+2.2 H₂ O: C, 33.34; H, 4.88; P, 6.14;S, 6.36 Found: C, 33.34; H, 4.94; P, 5.99; S, 6.17

96. 1-phosphono-7-(4-pentylphenoxy)-1-heptanesulfonic acid, tripotassiumsalt;

Mass Spec (ion spray, + ions) m/z 464 (M+4H-3K+CH₃ CN), 461 (M+3H-2K),423 (M+4H-3K).

Anal. Calcd for C₁₈ H₂₈ K₃ O₇ PS+1.34 H₂ O: C, 38.55; H, 5.51; P, 5.52;S, 5.72 Found: C, 38.55; H, 5.66; P, 5.11; S, 6.01

97. α-phosphono-3'-propyl[1,1'-biphenyl]-4-butanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 565 (M+K), 527 (M+H), 89 (M-K+2H), 451(M-2K+3H)

Anal. Calcd for C₁₉ H₂₂ O₆ PSK₃ +1.0 H₂ O: C, 41.84; H, 4.45; S, 5.88;P, 5.68 Found: C, 41.84; H, 4.74; S, 6.14; P, 5.30

98. 4-(4-methylphenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 553 (M+K), 515 (M+H), 477 (M+2H-K)

Anal. Calcd for C₁₇ H₁₈ K₃ O₇ PS+1.7 H₂ O: C, 37.45; H, 3.96; P, 5.68;S, 5.88 Found: C, 37.38; H, 3.79; P, 5.38; S, 6.24

99. (E,E)-4,8,12-trimethyl-1-phosphono-3,7,11-tridecatriene-1-sulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 533 (M+K), 495 (M+H), 457 (M+2H-K)

Anal. Calcd for C₁₆ H₂₆ PSO₆ K₃ +1.00 H₂ O: C, 37.49; H, 5.50; P, 6.04;S, 6.25 Found: C, 37.40; H, 5.54; P, 6.08; S, 6.69

100. (E)-6-methyl-7-phenoxy-1-phosphono-5-heptenyl-1-sulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 517 (M+K), 479 (M+H), 441 (M-K+2H)

Anal. Calcd for C₁₄ H₁₈ O₇ PSK₃ +2.0 H₂ O: C, 32.67; H, 4.31; P, 6.02;S, 6.23 Found: C, 32.28; H, 4.25; P, 5.78; S, 6.11

101. (E)-6-methyl-7-(4-propylphenoxy)-1-phosphono-5-heptene-1-sulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 521 (M+H), 483 (M-K+2H), 445 (M-2K+3H)

Anal. Calcd for C₁₇ H₂₅ O₇ PSK₂ +1.85 H₂ O: C, 39.57; H, 5.61; P, 6.00;S, 6.21 Found: C, 39.18; H, 5.23; P, 6.14; S, 6.41

102. (E)-6-methyl-8-(3-methylphenyl)-1-phosphono-5-octenyl-1-sulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 529 (M+K), 491 (M+H), 453 (M-K+2H)

Anal. Calcd for C₁₆ H₂₂ O₆ PSK₃ +1.03 H₂ O: C, 37.74; H, 4.76; P, 6.08;S, 6.30 Found: C, 37.99; H, 5.21; P, 5.90; S, 6.60

103. (E)-6-methyl-1-phosphono-7-(3-propylphenoxy-5-heptene-1-sulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 521 (M+H), 483 (MK-K+2H), 445 (M-2K+3H), 407(M-3K+4H)

Anal. Calcd for C₁₇ H₂₄ O₇ PSK₃ +0.64 H₂ O: C, 38.37; H, 4.79; P, 5.82;S, 6.02 Found: C, 38.37; H, 5.12; P, 5.83; S, 5.81

104. (E)-6-methyl-7-(2-methylphenoxy)-1-phosphono-5-heptene-1-sulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 531 (M+K), 493 (M+H), 455 (M-K+2H)

Anal. Calcd for C₁₅ H₂₀ O₇ PSK₃ +1.46 H₂ O: C, 34.72; H, 4.45; P, 5.97;S, 6.18 Found: C, 34.72; H, 4.90; P, 5.58; S, 5.92

105. (E,E)-6,10,14-trimethyl-1-phosphono-5,9-pentadecadiene-1-sulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 563 (M+K), 525 (M+H), 487 (M+2H-K)

Anal. Calcd for C₁₈ H₃₂ O₆ PSK₃ +2.0 H₂ O: C, 38.55; H, 6.47; P, 5.52;S, 5.72 Found: C, 38.93; H, 6.87; P, 5.62; S, 5.49

106. 4'-phenoxy-α-phosphono[1,1'-biphenyl]butanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 577 (M+H), 539 (MK+2H), 501 (M-2K+3H)

Anal. Calcd for C₂₂ H₃₀ K₃ O₇ PS+1.6 H₂ O: C, 43.64; H, 3.86; P, 5.11;S, 5.29 Found: C, 43.73; H, 3.97; P, 4.71; S, 5.30

107. α-phosphono-4'-propyl[1,'-biphenyl]-4-propanesulfonic acid,tripotassium salt

Mass Spec (FAB, + ions) m/z 551 (M+K), 513 (M+H), 475 (M-K+2H)

Anal. Calcd for C₁₈ H₂₀ K₃ O₆ PS+4.1 H₂ O: C, 36.90; H, 4.84; P, 5.29;S, 5.47 Found: C, 36.90; H, 4.68; P, 5.05; S, 5.67

108. 3-(4-methylphenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 477 (M-K+2H), 515 (M+H), 553 (M+K)

Anal. Calcd for C₁₇ H₁₈ K₃ O₇ PS+2.1 H₂ O: C, 36.96; H, 4.05; P, 5.61;S, 5.80 Found: C, 37.27; H, 4.42; P, 5.43; S, 5.42

109. (E)-8-phenyl-1-phosphono-5-octene-1-sulfonic acid, tripotassiumsalt;

Mass spec (FAB, + ions) m/z 501 (M+K), 463 (M+H), 425 (M-K+2H)

Anal. Calcd for C₁₄ H₁₈ O₆ PSK₃ +3.0 H₂ O: C, 32.50; H, 4.69; P, 5.99;S, 6.20 Found: C, 32.50; H, 4.73; P, 6.03; S, 6.40

110. 2'-methoxy-α-phosphono-4'-propyl[1,1'-biphenyl]-4-butanesulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 519 (M+2H-K), 481 (M+3H-2K)

Anal. Calcd for C₂₀ H₂₄ K₃ O₇ PS+2.3 H₂ O: C, 40.16; H, 4.82; P, 5.18;S, 5.36 Found: C, 40.14; H, 4.83; P, 4.79; S, 5.44

111.(E,E)-6,10-dimethyl-12-phenyl-1-phosphono-5,9-dodecadiene-1-sulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 583 (M+K), 545 (M+H), 507 (M+2H-K)

Anal. Calcd for C₂₀ H₂₈ O₆ PSK₃ +0.8 H₂ O: C, 42.96; H, 5.34; P, 5.54;S, 5.73 Found: C, 42.96; H, 5.74; P, 5.65; S, 5.72

112. (E)-6-methyl-7-(phenylthio)-1-phosphono-5-heptenyl-1-sulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 533 (M+K), 495 (M+H), 457 (M-K+2H), 419(M-2K+3H)

Anal. Calcd for C₁₄ H₁₈ O₆ PS₂ K₃ +3.8 H₂ O: C, 29.87; H, 4.58; P, 5.50;S, 11.39 Found: C, 29.87; H, 4.73; P, 5.48; S, 11.52

113. 3-phenoxy-α-phosphonobenzenepropanesulfonic acid, tripotassiumsalt;

Mass Spec (FAB, + ions) m/z 499 (M+2H-K), 487 (M+H), 525 (M+K)

Anal. Calcd for C₁₅ H₁₄ K₃ O₇ PS+1.6 H₂ O: C, 34.95; H, 3.36; P, 6.01;S, 6.22 Found: C, 34.91; H, 3.31; P, 5.93; S, 6.23

114.2'-(methoxymethoxy)-α-phosphono-4'-propyl[1,1'-biphenyl]-4-butanesulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 625 (M+K), 586 (M+H), 549 (M+2H-K)

Anal. Calcd for C₂₁ H₂₆ K₃ O₈ PS+2.4 H₂ O: C, 40.03; H, 4.93; P, 4.92;S, 5.09 Found: C, 40.03; H, 5.03; P, 4.80; S, 5.42

115. 2'-hydroxy-α-phosphono-4'-propyl[1,1'-biphenyl]-4-butanesulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 581 (M+K), 543 (M+H), 467 (M+2H-K)

Anal. Calcd for C₁₉ H₂₂ PSO₇ K₃ +2.7 H₂ O: C, 38.59; H, 4.67; P, 5.24;S, 5.42 Found: C, 38.59; H, 4.58; P, 5.07; S, 5.56

116. α-phosphono-4'-(2-pyridinyl) [1,1'-biphenyl]-butanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 562 (M+H), 524 (M-K+2H), 486 (M-2K+3H)

Anal. Calcd for C₂₁ H₁₉ NO₆ PSK₃ +2.5 H₂ O: C, 41.57; H, 3.99; N, 2.31;P, 5.10; S, 5.28 Found: C, 41.48; H, 3.90; N, 2.40; P, 4.78; S, 5.27

117. (E)-6-methyl-7-phenyl-1-phosphono-5-heptane-1-sulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 501 (M+K), 463 (M+H), 425 (M-K+2H)

Anal. Calcd for C₁₄ H₁₈ O₆ PSK₃ +2.9 H₂ O: C, 32.67; H, 4.66; P, 6.02;S, 6.23 Found: C, 32.67; H, 4.63; P, 6.13; S, 6.02

118. α-fluoro-3-phenoxy-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 519 (M+H), 481 (M+2H-K), 440 (M+3H-2K)

Anal. Calcd for C₁₆ H₁₅ FO₇ PSK₃ +1.4 H₂ O: C, 35.33; H, 3.30; P, 5.69;S, 5.89 Found: C, 35.73; H, 3.71; P, 5.77; S, 6.09

119. (E)-6methyl-8-(2-methylphenyl)-1-phosphono-5-octene-1-sulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 529 (M+K), 491 (M+H), 453 (M-K+2H)

Anal. Calcd for C₁₆ H₂₂ PSO₆ K₃ +2.2 H₂ O: C, 36.21; H, 5.02; P, 5.84;S, 6.04 Found: C, 36.29; H, 4.96; P, 5.44; S, 6.40

120. 3-(2-naphthalenyloxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 513 (M-K+2H), 551 (M+H), 589 (M+K)

Anal. Calcd for C₂₀ H₁₈ K₃ O₇ PS+3.8 H₂ O: C, 38.80; H, 4.17; P, 5.00;S, 5.18 Found: C, 38.69; H, 4.04; P, 5.10; S, 4.96

121. (E)-6-methyl-1-phosphono-8-(4-propylphenyl)-5-octene-1-sulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 557 (M+K), 519 (M+H), 481 (M-K+2H)

Anal. Calcd for C₁₈ H₂₆ PSO₆ K₃ +3.36 mol H₂ O: C, 37.32; H, 5.69; P,5.35; S, 5.53 Found: C, 37.32; H, 5.68; P, 5.46; S, 5.66

122. (E)-8-(3-methoxyphenyl)-6-methyl-1-phosphono-5-octene-1-sulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 545 (M+K), 507 (M+H), 469 (M-K+2H)

Anal. Calcd for C₁₆ H₂₂ PSO₇ K₃ +2.3 H₂ O: C, 35.04; H, 4.90; P, 5.65;S, 5.85 Found: C, 35.04; H, 5.19; P, 5.54; S, 5.41

123. α-phosphono-4'-(1-piperidinyl) [1,1'-biphenyl]-4-butanesulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 606 (M+K), 568 (M+H), 530 (M-K+2H), 492(M-2K+3H)

Anal. Calcd for C₂₁ H₂₅ K₃ NO₆ PS+2.7 H₂ O: C, 40.92; H, 4.97; N, 2.27;P, 5.02; S, 5.20 Found: C, 40.93; H, 4.96; N, 2.00; P, 4.93; S, 5.53

124. ζ-methyl-α-phosphono-4-propylbenzeneoctanesulfonic acid,tripotassium salt;

Mass Spec (Electrospray, - ions) m/z 405(M-3K+2H)

Anal. Calcd for C₁₈ H₂₈ O₆ PSK₃ +1.92 H₂ O:

C, 38.93; H, 5.78; P, 5.58; S, 5.77 Found: C, 38.93; H, 6.05; P, 5.45;S, 5.90

125. ζ,2-dimethyl-α-phosphonobenzeneoctanesulfonic acid, tripotassiumsalt;

Mass Spec (Electrospray, - ions) m/z 377 (M-3K+2H)

Anal. Calcd for C₁₆ H₂₄ O₆ PSK₃ +1.2 H₂ O: C, 37.37; H, 5.17; P, 6.23;S, 6.02 Found: C, 37.87; H, 5.65; P, 6.10; S, 5.80

126. 3-(1-naphthalenyloxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 475 (M-2K+3H), 513 (M-K+2H), 551 (M+H), 589(M+K)

Anal. Calcd for C₂₀ H₁₈ K₃ O₇ PS+2.5 H₂ O: C, 40.32; H, 3.89; P, 5.20;S, 5.38 Found: C, 40.42; H, 4.17; P, 5.41; S, 5.09

127. 3-(cyclohexyloxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 545 (M+K), 507 (M+H), 469 (M-K+2H).

Anal. Calcd for C₁₆ H₂₂ O₇ PSK₃ +4.2 H₂ O: C, 32.98; H, 5.27; P, 5.32;S, 5.50 Found: C, 32.98; H, 5.25; P, 5.65; S, 5.18.

128. 3-(3-ethylphenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 491 (M-K+2H), 529 (M+H), 567 (M+K).

Anal. Calcd for C₁₈ H₂₀ K₃ O₇ PS+1.6 H₂ O: C, 38.78; H, 4.19; P, 5.56;S, 5.75 Found: C, 38.94; H, 4.47; P, 5.32; S, 5.31.

129. α-phosphono-3-[3-(trifluoromethyl)phenoxy]benzenebutanesulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 431 (M-K+2H), 569 (M+H), 607 (M+K)

Anal. Calcd for C₁₇ H₁₅ F₃ K₃ O₇ PS+1.6 H₂ O: C, 34.18; H, 3.07; F,9.54; P, 5.18; S, 5.37 Found: C, 34.21; H, 3.15; F, 9.20; P, 5.02; S,5.51

130. (E)-6-methyl-1-phosphono-8-[3-(trifluoromethyl)phenyl]-5-octene-1-sulfonic acid, tripotassium salt;

Mass Spec (Ion Spray, - ions) m/z 429 (M-3K+2H), 411 (M-3K+2H-H₂ O).

Anal. Calcd for C₁₆ H₁₉ F₃ K₃ PSO₆ +2.3 H₂ O: C, 32.78; H, 4.06; P,5.28; S, 5.47 Found: C, 32.78; H, 4.41; P, 5.55; S, 5.86.

131. 3-phenoxy-α-phosphonobenzenepentanesulfonic acid, tripotassiumsalt;

Mass Spec (FAB, + ions) m/z 477 (M+2H-K), 515 (M+H), 553 (M+K)

Anal. Calcd for C₁₇ H₁₈ K₃ O₇ PS+1.5 H₂ O: C, 37.95; H, 3.86; P, 5.76;S, 5.96 Found: C, 37.95; H, 4.24; P, 5.56; S, 5.97.

132. 3-[2-(3-methylbutyl)phenoxy]-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, +ion) m/z 533 (M-K+2H), 571 (M+H), 609 (M+K)

Anal. Calcd for C₂₁ H₂₆ K₃ O₇ PS+1.5 H₂ O: C, 42.19: H, 4.89; P, 5.18;S, 5.36 Found: C, 42.33; H, 5.15; P, 4.96; S, 5.02.

133. 3-[2-(3-methyl-2-butenyl)phenoxy]-α-phosphonobenzenebutanesulfonicacid, tripotassium salt;

Mass Spec (FAB, +ion) m/z 569 (M+H), 607 (M+K)

Anal. Calcd for C21H24K307PS⁺ 2-2 H20: C, 41.46; H, 4.71; P, 5.09; S,5.27 Found: C, 41.64; H, 4.73; P, 5.11; S, 4.77.

134. α-[bis[1-(1-oxopropoxy)ethoxy]phos-,phinyl]-3-phenoxybenzenebutanesulfonic acid, monopotassium salt;

Mass Spec (FAB, + ions) 663 (M+K)

Anal. Calcd for C₂₆ H₃₄ KO₁₁ PS: C, 49.99; H, 5.49; P, 4.96; S, 5.13Found: C, 49.93; H, 5.54; P, 5.08; S, 5.44.

135.(E)-8-([1,1'-biphenyl]-4-yl)-6-methyl-1-phosphono-5-octene-1-sulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/e 591 (M+K), 553 (M+H), 515 (M-K+2H)

Anal. Calcd for C₂₁ H₂₄ PSO₆ K₃ +1.34 mol H₂ O: C, 43.72; H, 4.66; P,5.37; S, 5.56 Found: C, 43.72; H, 4.97; P, 5.31; S, 5.59.

136. 3-(2-cyclohexen-1-yloxy)-(α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/e 543 (M+K), 505 (M+H), 467 (M-K+2H)

Anal. Calcd for C₂₆ H₂₀ O₇ PSK₃ +5.22 H₂ O: C, 32.10; H, 5.12; P, 5.17;S, 5.36 Found: C, 32.10; H, 4.84; P, 4.90; S, 5.71.

137. (E)-6-methyl-8-(2-naphthalenyl)-1-phosphono-5-octene-1-sulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/e 565 (M+K), 527 (M+H)

Anal. Calcd for C₁₉ H₂₂ PSO₆ K₃ +4.10 mol H₂ O: C, 38.00; H, 5.07; P,5.16; S, 5.34 Found: C, 38.39; H, 4.87; P, 5.31; S, 4.94.

138. 3-(phenylmethoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec 515 (M+H), 477 (M-K+2H), 439 (M-2K+3H)

Anal. Calcd for C₁₇ H₁₈ O₇ PSK₃ +3.5 H₂ O: C, 35.34; H, 4.36; P, 5.36;S, 5.55 Found: C, 35.34; H, 4.40; P, 5.03; S, 5.26.

139. 6-([1,1'-biphenyl]-4-yl)-α-phosphono-3-pyridinebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) 600 (M+K), 562 (M+H), 524 (M-K+2H), 486(M-2K+3H)

Anal. Calcd for C₂₁ H₁₉ NO₆ PSK₃ +2.3 H₂ O: C, 41.82; H, 3.94; N, 2.32;P, 5.14; S, 5.32 Found: C, 42.21; H, 4.34; N, 2.30; P, 5.02; S, 5.34.

140. 3-(4-chlorophenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 573 (M+K), 535 (M+H), 497 (M-K+2H), 463(M-K-Cl+3H)

Anal. Calcd for C₁₆ H₁₅ ClO₇ PS.3K+0.89 H₂ O: C, 34.87; H, 3.07; P,5.62; S, 5.82; Cl, 6.43 Found: C, 35.28; H, 3.51; P, 5.48; S, 5.97; Cl,6.25.

141. 3-(3-chlorophenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, +ion) m/z 459 (M-2K+3H), 497 (M-K+2H), 535 (M+H)

Anal. Calcd for C₁₆ H₁₅ ClK₃ O₇ PS+1.5 H₂ O: C, 34.19; H, 3.23; P, 5.51;S, 5.70 Found: C, 34.23; H, 3.66; P, 5.25; S, 5.91.

142. (E)-6-methyl-1-phosphono-8-(2-pyridinyl)-5-octene-1-sulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 516 (M+K), 478 (M+H), 440 (M-K+2H)

Anal. Calcd for C₁₄ H₁₉ NPSO₆ K₃ +1.30 H₂ O: C, 33.58; H, 4.34; N, 2.80;P, 6.19 S, 6.40 Found: C, 33.54; H, 4.41; N, 2.84; P, 6.05 S, 6.07

143. 2-methoxy-5-phenoxy-α-phosphonobenzenebutanoic acid, tripotassiumsalt;

Mass Spec (FAB, + ions) m/z 569 (M+K), 531 (M+H), 493 (M-K+2H), 455(M-2K+3H)

Anal. Calcd for C₁₇ H₁₈ K₃ O₈ PS+1.2 H₂ O: C, 36.94; H, 3.73; P, 5.60;S, 5.80 Found: C, 37.37; H, 4.17; P, 5.36; S, 5.38.

144. (E,E)-1-[bis[2-methyl-1-(1-oxopropoxy)propoxy]phosphinyl]-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, monopotassium salt;

Mass Spec (FAB, + ions) 703 (M+H), 741 (M+K)

Anal. Cald for C₃₂ H₅₆ KO₁₀ PS: C, 54.68; H, 8.03; P, 4.41; S, 4.56Found: C, 54.66; H, 8.07; P, 4.37; S, 4.37.

145. ζ-methyl-α-phosphono[1,1'-biphenyl]-4-octanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/e (M+K), 555 (M+H), 517 (M-K+2H)

Anal. Calcd for C₂₁ H₂₆ PSO₆ K₃ +2.47 mol H₂ O: C, 42.09; H, 5.20; P,5.17; S, 5.35 Found: C, 42.09; H, 5.18; P, 4.77; S, 5.02.

146. 4-(2-phenyl-5-pyridinyl)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 600 (M+K), 562 (M+H), 524 (M-K+2H)

Anal. Calcd for C₂₁ H₁₉ NO₆ PSK₃ +1.9 H₂ O: C, 42.32; H, 3.86; N, 2.35;S, 5.38 P, 5.20 Found: C, 42.32; H, 4.21; N, 2.37; S, 5.27 P, 5.22.

147.α-[bis[1-(2,2-dimethyl-1-oxopropoxy)ethoxy]phinyl]-3-phenoxybenzenebutanesulfonicacid, monopotassium salt;

Mass Spec (FAB, + ions) m/z 719 (M+K)

Anal. Calcd for C₃₀ H₄₂ KO₁₁ PS+0.5 H₂ O: C, 52.24; H, 5.28; P, 4.49; S,4.65 Found: C, 52.42; H, 6.21; P, 4.65; S, 5.39.

148. 5-phenoxy-α-phosphono-2-thiophenebutanesulfonic acid, tripotassiumsalt;

Mass Spec (FAB, + ions) m/z 507 (M+H), 469 (M-K+2H), 431 (M-2K+3H)

Anal. Calcd for C₁₄ H₁₄ O₇ PS₂ K₃ +2.04 H₂ O: C, 30.95; H, 3.35; P,5.70; S, 11.80 Found: C, 30.95; H, 3.37; P, 5.33; S, 11.99.

149. 3-[2-(2-methoxyethyl)phenoxy]-α-phosphonobenzenebutanesulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 597 (M+K), 559 (M+H), 543 (M-K+Na+H), 521(M-K+2H), 483 (M-2K+3H)

Anal. Calcd for C₁₉ H₂₂ O₈ PS.3K+1.15 H₂ O: C, 39.38; H, 4.23; P, 5.34;S, 5.53 Found: C, 39.38; H, 4.51; P, 4.93; S, 5.34.

150. (E,E)-1-[bis[1-(benzoyloxy)ethoxy]phosphinyl]-6,10,14-trimethyl-5,9,13-pentadecatriene-1-sulfonicacid, monopotassium salt;

Mass Spec (FAB, + ions) 781 (M+K)

Anal. Calcd for C₃₆ H₄₈ KO₁₀ PS+0.3 H₂ O: C, 57.80; H, 6.54; P, 4.14; S,4.29 Found: C, 57.80; H, 6.43; P, 4.00; S, 3.23.

151.(E,E)-α-[bis[2-methyl-1-(1-oxopropoxy)propoxy]phosphinyl]-3-phenoxybenzenebutanesulfonicacid, monopotassium salt;

Mass Spec (FAB, + ions) m/z 719 (M+K)

Anal. Calcd for C₃₀ H₄₂ KO₁₁ PS: C, 52.93; H, 6.22; P, 4.55; S, 4.71Found: C, 52.86; H, 6.33; P, 4.28; S, 5.10.

152. 3-[2-(2-propenyl)phenoxy]-(α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass spec (FAB, +ion) m/z 465 (M-2K+3H), 503 (M-K+2H), 541 (M+H), 579(M+K)

Anal. Calcd for C₁₉ H₂₀ K₃ O₇ PS+2.7 H₂ O: C, 38.72; H, 4.34; P, 5.26;S, 5.44 Found: C, 38.79; H, 4.45; P, 5.00; S, 5.08.

153. 2-(methoxymethoxy)-5-phenoxy-α-phosphonobenzenebutanoic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 599 (M+K), 561 (M+H), 523 (M-K+2H)

Anal. Calcd for C₁₈ H₂₀ K₃ O₉ PS+2.9 H₂ O: C, 35.24; H, 4.25; P, 5.05;S, 5.23 Found: C, 35.24; H, 4.13; P, 4.84; S, 5.57.

154. α-phosphono-3-(2-pyridinyloxy)benzenebutanesulfonic acid,tripotassium salt;

Mass Spec m/z 540 (M+K), 502 (M+H), 464 (M-K+2H)

Anal. Calcd for C₁₅ H₁₅ NO₇ PSK₃ +2.63 H₂ O: C, 32.82; H, 3.72; N, 2.55;P, 5.64; S, 5.84 Found: C, 32.87; H, 4.12; N, 2.50; P, 5.38; S, 6.22.

155. 3-[2-phenylmethyl)phenoxy]-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec 629 (M+K), 591 (M+H), 553 (M-K+2H), 515 (M-2K+3H)

Anal. Calcd for C₂₃ H₂₂ K₃ O₇ PS: C, 45.32; H, 3.98; N, 0.00; S, 5.26;P, 5.08 Found: C, 45.32; H, 4.25; N, 0.24; S, 5.54; P, 4.84.

156. δ-methyl-3-phenoxy-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec. (FAB, + ions) m/z 515 (M+H), 553 (M+K)

Anal. Calcd for C₁₇ H₁₈ K₃ O₇ PS+2.5 H₂ O: C, 36.48; H, 4.14; P, 5.53;S, 5.73 Found: C, 36.50; H, 3.98; P, 5.37; S, 5.47.

157. 3-(3-fluorophenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, +ion) m/z 481 (M-K+2H), 519 (M+H), 557 (M+K)

Anal. Calcd for C₁₆ H₁₅ FK₃ O₇ PS.2.4 H₂ O: C, 34.20; H, 3.55; P, 5.51;S, 5.71 Found: C, 34.21; H, 3.45; P, 5.36; S, 6.04.

158. 3-(4-fluorophenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) 557 (M+K), 519 (M+H), 481 (M-K+2H), 443(M+2K+3H)

Anal. Calcd for C₁₆ H₁₅ FO₇ PSK₃ +2.0 H₂ O: C, 34.65; H, 3..45; S, 5.78;P, 5.58; F, 3.43 Found: C, 34.92; H, 3.88; S, 6.12; P, 5.59; F, 3.48.

159.α-[bis[1-(2-methyl-1-oxopropoxy)ethoxy]phosphinyl]-3-phenoxybenzenebutanesulfonicacid, monopotassium salt;

Mass Spec (FAB, + ions) m/z 691 (M+K)

Anal. Calcd for C₂₈ H₃₈ KO₁₁ PS: C, 51.52; H, 5.87; P, 4.75; S, 4.91Found: C, 51.65; H, 5.93; P, 4.63; S, 5.89.

160. 4-(2-benzoxazolyl)-α-phosphinylbenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) 526 (M+K), 488 (M+H), 450 (M-K+2H)

Anal. Calcd for C₁₇ H₁₅ NO₇ PSK₃.2.22 H₂ O: C, 36.10; H, 3.46; N, 2.48;S, 5.67; P, 5.48 Found: C, 35.98; H, 3.66; N, 2.60; S, 5.46; P, 5.53.

161.α-[bis[2-methyl-1-(2-methyl-1-oxo-propoxy)propoxy]phosphinyl]-3-phenoxybenzenebutanesulfonicacid, monopotassium salt;

Mass Spec (FAB, + ions) m/z 709 (M+K)

Anal. Calcd for C₃₂ H₄₆ KO₁₁ PS: C, 54.22; H, 6.54; P, 4.37; S, 4.52Found: C, 53.98; H, 6.57; P, 3.86; S, 5.31.

162.α-[bis[1-(1-oxopropoxy)propoxy]phosphinyl]-3-phenoxybenzenebutanesulfonicacid, monopotassium salt;

Mass Spec (FAB, + ions) m/z 691 (M+K)

Anal. Calcd for C₂₈ H₃₈ KO₁₁ PS: C, 51.52; H, 5.87; P, 4.75; S, 4.91Found: C, 51.75; H, 5.85; P, 4.54; S, 5.84.

163. 3-(3,4-dichlorophenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, +ion, for ³⁵ Cl) m/z 531 (M-K+2H), 569 (M+H), 607 (M+K),(Cl isotope pattern)

Anal. Calcd for C₁₆ H₁₄ Cl₂ K₃ O₇ PS.1.6 H₂ O: C, 32.12; H, 2.90; P,5.18; S, 5.36 Found: C, 32.10; H, 3.15; P, 5.16; S, 5.71.

164. 3-(2,3-dichlorophenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, +ion, for ³⁵ Cl) m/z 533 (M-K+2H), 569 (M+H), 607 (M+K),(Cl isotope pattern)

Anal. Calcd for C₁₆ H₁₄ Cl₂ O₇ PS.2.2 H₂ O: C, 31 .55; H, 3.04; P, 5.09;S, 5.26 Found: C, 31 .54; H, 3.17; P, 4.75; S, 5.51.

165. 3-(2-phenoxyphenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, +ion) m/z 555 (M-K+2H), 593 (M+H), 631 (M+K)

Anal. Calcd for C₂₂ H₂₀ K₃ O₈ PS+1.8 H₂ O: C, 42.27; H, 3.81; P, 4.95;S, 5.13 Found: C, 42.25; H, 3.91; P, 5.25; S, 4.88.

166. 3-(2-benzoylphenoxy)-α-phosphonobenzenesulfonic acid, tripotassiumsalt;

Mass Spec (FAB, +ion) m/z 567 (M-K+2H), 605 (M+H), 643 (M+K)

Anal. Calcd for C₂₃ H₂₀ K₃ O₈ PS+3.1 H₂ O: C, 41.82; H, 4.00; P, 4.69;S, 4.85 Found: c, 41.86; H, 3.88; P, 4.69; S, 4.86.

167. (Z)-6-methyl-8-phenyl-1-phosphono-5-octene-1-sulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 515, (M+K), 477 (M+H)

Anal. Calcd for C₁₅ H₂₀ PSO₆ K₃ +1.8 H₂ O: C, 35.36; H, 4.68; P, 6.08;S, 6.29 Found: C, 35.36; H, 4.67; P, 5.89; S, 6.00.

168. (E)-8-(2-fluorophenyl)-6-methyl-1-phosphono-5-octene-1-sulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 533 (M+K), 495 (M+H), 457 (M-K+2H)

Anal. Calcd for C₁₅ H₁₉ FPSO₆ K₃ +3.50 H₂ O: C, 32.35; H, 4.69; P, 5.56;S, 5.76 Found: C, 32.35; H, 4.69; P, 5.63; S, 5.76.

169. 3-(4-methoxyphenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, + ions) m/z 569 (M+K), 531 (M+H), 493 (M-K+2H), 455(M-2K+3H)

Anal. Calcd for C₁₇ H₁₈ O₈ PS.3K +1.71 H₂ O: C, 36.36; H, 3.85; P, 5.52;S, 5.71 Found: C, 36.78; H, 4.00; P, 5.13; S, 5.54.

170. 3-(3-methoxyphenoxy)-α-phosphonobenzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, +ion) m/z 531 (M+H), 569 (M-K)

Anal. Calcd for C₁₇ H₁₈ K₃ O₈ PS+1.7 H₂ O: C, 36.38; H, 3.84; P, 5.52;S, 5.71 Found: C, 36.43; H, 4.16; P, 5.43; S, 5.66.

171. 3-(2-propoxyphenoxy)-α-phosphonobenzenebutanoic acid, tripotassiumsalt;

Mass Spec (FAB, + ions) m/z 597 (M+K), 559 (M+H), 521 (M-K+2H)

Anal. Calcd for C₁₉ H₂₂ K₃ O₈ PS+1.1 H₂ O: C, 39.50; H, 4.21; P, 5.36;S, 5.55 Found: C, 39.50; H, 4.49; P, 5.09; S, 5.31.

172. α-phosphono-3-(2-propylphenoxy)benzenebutanesulfonic acid,tripotassium salt;

Mass Spec (FAB, +ion) m/z 505 (M-K+2H), 543 (M+H), 581 (M+K)

Anal. Calcd for C₁₉ H₂₂ K₃ O₇ PS+2.0 H₂ O: C, 39.43; H, 4.53; P, 5.35;S, 5.54 Found: C, 39.44: H, 4.42; P, 5.21; S, 5.85.

173. 3-[2-(2-ethoxymethyl)phenoxy]-α-phosphonobenzenebutanesulfonicacid, tripotassium salt;

Mass Spec (FAB, + ions) m/z 597 (M+K), 559 (M+H), 543 (M-K+Na+H), 521(M-K+2H), 1041 (2M+K), 1079 (2M+2K-H), 1117 (2M+3K-2H)

Anal. Calcd for C₁₉ H₂₂ O₈ PS.3K+1.43 H₂ O: C, 39.05; H0 4.29: P, 5.30;S, 5.49 Found: C, 39.05; H, 4.31; P, 5.11; S, 5.10.

EXAMPLE 174

α-[Bis[(2,2-Dimethyl-1-oxopropoxy)methoxy]phosphinyl]-3-phenoxybenzenebutanesulfonicacid, monopotassium salt

A.α-[Bis[2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]-3-phenoxybenzenebutanesulfonicacid, cyclohexyl ester

Bromotrimethylsilane (3.61 g, 23.63 mmol, 4 eq.) was added dropwise to asolution of Example 40, Part E ester (3.10 g, 5.90 mmol) andallyltrimethylsilane (4.71 g, 41.3 mmol) in dichloromethane (20 mL) atRT under argon. The clear reaction mixture was stirred at RT for 48 h,concentrated and pumped at high vacuum for 4 h to give a colorless oil.

The crude silyl ester prepared above (3.55 g, ≈5.88 mmol) was dissolvedin 1N KOH (12.7 mL, 12.7 mmol) over 10 min, then added slowly withvigorous stirring to a solution of silver nitrate (2.17 g, 12.76 mmol)in water (40 mL) under argon in the dark. The resulting white gum wasdiluted with 40 mL of water, extracted with toluene (4×75 mL) and driedover Na₂ SO₄. The organics were filtered and concentrated to a thickgum. The gum was diluted with 80 mL of toluene, cooled to 0° C. andtreated with 2,2-dimethylpropanoic acid, iodomethyl ester (3.87 g, 16.00mmol) in 20 mL of toluene over 15 min. After 5 min. at 0° C., a solidprecipitated out of the solution. The reaction was stirred an additional0.5 h and warmed to room temperature. The mixture was stirred withCelite (4 g) for 6 min., filtered through a pad of Celite andconcentrated to provide a yellow oil. The oil was purified by flashcolumn chromatography on silica gel (200 g) eluting with (1.5 L) 20:80ethyl acetate/hexane followed by (0.5 L) 40:60 ethyl acetate/hexane toprovide 2.60 g (65%) of title compound as a colorless oil.

TLC Silica gel (3:7 ethyl acetate/hexanes) R_(f) =0.50.

B.α-[Bis[(2,2-Dimethyl-1-oxopropoxy)methoxy]phosphinyl]-3-phenoxybenzenebutanesulfonicacid, monopotassium salt

To a mixture of 1.07 g (11.00 mmol) of KOAc in 40 mL of a 9:1trifluoroethanol/water (v/v) solution was added 2.50 g (3.59 mmol) ofPart A compound. After a homogeneous solution was obtained (≈15 min.),the solution was heated to 40° C. (bath temp.) for 20 h and the solventremoved under reduced pressure. The remainder was diluted with water (5mL) and concentrated. The residue was diluted with ethyl acetate, washedwith solutions of KHCO₃ (2×8 mL) and KCl (1×10 mL), dried over anhydrousKCl and evaporated to provide a pale yellow oil. The oil was dilutedwith 15 mL of water (a soapy slurry formed) and freeze dried to provide2.02 g (86%) of title compound as a white lyophilate.

TLC Silica gel (1:9 methanol/dichloromethane) R_(f) =0.60.

IR (KBr) 3488, 3063, 2974, 1753, 1584, 1485, 1460, 1447, 1397, 1370,1250, 1215, 1163, 1140, 1069, 1045, 1022, 1003, 963 cm⁻¹.

¹ H NMR (DMSO, 300 MHz): δ7.33 (t, 2H, J=8.5 Hz) 7.25 (t, 1H, J=8.5 Hz)7.15 (t, 1H, J=8.0 Hz) 6.93 (m, 3H) 6.80 (s, 1H) 6.75 (d, 1H, J=9.0 Hz)5.45 (m, 4H) 3.15 (dt, 1H, J=19.0, 5.0 Hz) 2.50 (t, 2H, J=7.0 Hz) 1.90,1.80 (two m, 4H) 1.10 (s, 3H, H₁₂) 1.55 (two s, 18H)ppm.

Mass Spec (FAB, + ions) m/z 691 (M+K), 615 (M-K+2H), 445 (M-C₁₂ H₂₂ O₅+K).

Anal. Calcd for C₂₈ H₃₈ O₁₁ SPK: C, 51.52; H, 5.87; P, 4.75; S, 4.91Found: C, 51.38; H, 5.93; P, 4.65; S, 4.90.

EXAMPLE 175

(S)-(-)-3-Phenoxy-α-phosphonobenzenebutanesulfonic acid, tripotassiumsalt

A. (1R,2R)-N,N'-Dimethyl-1,2-cyclohexanediamine

Preparation of the title compound was carried out as described byHanessian, S. et. al. J. Amer. Chem. Soc. 1984, 106, 5754-5756, andAlexakis, A. et. al. J. Org. Chem. 1992, 57, 1224-237, Galsbol, F. etal., Acta Chem. Scand. 1972, 26, 3605 and Onuma, K. et. al., Bull. Chem.Soc. Jpn. 1980, 53, 2012.

[α_(spec) ]_(D) ²⁰ =-150° CHCl₃, (C=1); Literature

[α_(spec) ]_(D) ²⁰ =-147°.

B.[3aR-(3aα,7aβ)]-Octahydro-1,2,3-trimethyl-1H-1,3,2-benzodiazaphosphole,2-oxide

To a solution of 4.0 g (28.1 mmol, 1 eq.) of Part A diamine and 7.92 mL(56.8 mmol, 2.02 eq) of triethylamine in 64 mL of benzene at RT wasadded a solution of 3.74 g (28.1 mmol, 1 eq.) of methylphosphonicdichloride in 40 mL of benzene over 40 minutes. The heterogeneousmixture was stirred for 90 minutes at RT and then filtered through a padof Celite, rinsing well with ethyl acetate. Concentration of the organicsolution afforded 5.67 g of a yellow oil. Flash chromatography of theoil on silica gel (100 g), eluting with 7% methanol in ethyl acetate,afforded 4.59 g (81%) of the title compound as a white solid, m.p.61°-63° C.

TiC Silica gel (10% methanol in ethyl acetate): R_(f) 0.12.

C.[3aR-(3aα,7aβ)]-Octahydro-1,3-dimethyl-2-[4-(3-phenoxyphenyl)butyl]-1H-1,3,2-benzodiazaphosohole,2-oxide

To a solution of 2.0 g (9.9 mmol, 1 eq.) of Part B compound in 15 mL ofTHF at -78° C. was added dropwise 4.4 mL (10.9 mmol, 1.1 eq.) of 2.5Mn-BuLi in hexane. Addition of the alkyl lithium resulted in a gelatinousmixture to which 5 mL of THF was added. The resulting opaque whitesolution was stirred for 1 hour at -78° C. A solution of 3.8 g (11.9mmol, 1.2 eq.) of 3-(3-phenoxyphenyl)propyliodide in 10 mL of THF wasthen added dropwise over 20 minutes. The reaction was stirred at -78° C.for 2 hours, 0° C. for 1 hour and RT for 19 hours. The reaction wasquenched with methanol, diluted with ethyl acetate, washed with waterand dried (Na₂ SO₄). Concentration of the organic solution afforded 4.81g of the crude product as a yellow oil. Flash chromatography of the oilon silica gel (200 g), eluting with 5% methanol in ethyl acetate,afforded 3.78 g (92%) of the title compound as a viscous yellow oil.

TLC Silica gel (10% methanol in ethyl acetate): R_(f) 0.29.

D. [3aR-[2(R*),3aα,7aβ]]-[1-[[(Dimethylamino)thioxomethyl]thio]-4-(3-phenoxyphenyl)butyl]octahydro-1,3-dimethyl-2-1H-1,3,2-benzodiazamhosphole,2-oxide

and

E. [3aR-[2(S*),3aα,7β]]-[1-[[(Dimethylamino)thioxomethyl]thio]-4-(3-phenoxyphenyl)butyl]octahydro-1,3-dimethyl-2-1-H-1,3,2-benzodiazaphosphole,2-oxide

To a solution of 3.7 g (8.97 mmol, 1 eq) of Part C compound in 60 mL ofTHF at -75° C. (internal temperature) was added dropwise 3.95 mL (9.87mmol, 1.1 eq) of 2.5M n-BuLi in hexanes at a rate to keep temperaturebelow -70° C. (15 min). The reaction was stirred at -75° C. for 2 h. Thereaction was cooled to -90° C. (liquid nitrogen/methanol slush) and 2.59g (10.8 mmol, 1.2 eq) of tetramethylthiuram disulfide was added as asolid in small portions over 20 minutes. The reaction was stirred at-90° C. for 1 hour and then warmed to -70° C. (dry ice/methanol) andstirred for 2 hours. The reaction was quenched by the addition ofmethanol (5 mL), warmed to RT and diluted with ether. Concentration ofthe organic solution afforded 6.65 g of a yellow solid-oil mixture whichcontained title D α-(R) isomer and title E α-(S) isomer in a 1:3 ratio.Flash chromatography on silica gel (200 g), eluting with 2% methanol inethyl acetate, afforded 0.807 g (17%) of title D α-(R) isomer and 2.66 g(56%) of title E α-(S) isomer, each with >99% d.e. as judged by ³¹ PNMR.

³¹ P NMR(CDCl₃, 121 MHz, ref. to 10% H₃ PO₄, 0 ppm): title D α-(R)isomer 41.6 ppm; title E α-(S) isomer 39.3 ppm.

TLC Silica gel (10% methanol in ethyl acetate): For title D α-(R) isomerR_(f) 0.46; for title E α-(S) isomer R_(f) 0.37.

(10.% methanol in t-Butyl methyl ether): For title D α-(R) isomer R_(f)0.45; for title E α-(S) isomer R_(f) 0.33.

F.(S)-α-[[(Dimethylamino)thioxomethyl]thio]-3-phenoxybenzenebutanephosphonicacid

To a solution of 1.95 g (3.67 mmol, 1 eq) of title E α-(S) isomer in 35mL of acetonitrile was added 37 mL (110 mmol, 30 eq) of 3N hydrochloricacid. The homogeneous solution was stirred at RT for 13 hours. Thereaction was concentrated and the residue was dissolved in 20 mL ofwater and evaporated. A column of Biorad AG-50W-X8 ion exchange resin,H⁺ form (22 mL bed volume, 37 meq) was equilibrated initially with water(50 mL), followed by 50% aqueous isopropanol (50 mL). The residual oilwas dissolved in 25 mL of 30% aqueous isopropanol and eluted slowlythrough the resin with 30% aqueous isopropanol followed by evaporationto afford 1.47 g (94%) of the title compound as a clear viscous oil.

[α_(spec) ]_(D) ²⁰ +0.8° (c. 10, MeOH)

³¹ P NMR (CDCl₃, 121 MHz, ref. to 10% H₃ PO₄, 0 ppm): 30.5 ppm.

TLC Silica gel (6:3:1 n-propanol:ammonium hydroxide:water): R_(f) 0.59.

G. (S)-(-)-3-Phenoxy-α-phosphonobenzenebutanesulfonic acid tripotassiumsalt

To 1.44 g (3.39 mmol, 1 eq) of Part F α-(S) isomer was added 12 mL ofacetic acid and mixture was allowed to stir to effect completedissolution. A white precipitate formed after 15 minutes. To theheterogeneous reaction was added 1.35 mL of formic acid followed after 5minutes by 2.08 mL (20.3 mmol, 6 eq) of 30% hydrogen peroxide in water(exothermic:internal temperature increased to 38° C.). The reactionbecame cloudy after 30 sec and a yellow precipitate became visiblewithin 1 min. The reaction was monitored by reverse phase HPLC. After 7h, excess peroxide was decomposed by the slow addition of 622 μL (8.48mmol, 2.5 eq) of dimethyl sulfide (exothermic:internal temperatureincreased to 40° C.). The reaction was diluted with water, filtered andconcentrated. The residue was dissolved in water (25 mL), concentrated,then redissolved in water (10 mL) and the pH of the resulting solution(pH ≈1.95) was brought to pH 12 with 1N potassium hydroxide (12 mL). Thebasic solution was lyophilized. The lyophilate was dissolved in waterand chromatographed on CHP-20P gel (2.5 cm×25 cm) eluting initially withwater (1 L) followed by 10% CH₃ CN in water. Fractions containingproduct were analyzed by HPLC, then pooled and concentrated to afford aclear waxy residue which was dissolved in water, filtered andlyophilized to afford 1.42 g (82%) of the title compound as a whitelyophilate.

TLC Silica gel (6:3:1 n-propanol:ammonium hydroxide:water): R_(f) 0.21.

[α_(spec) ]_(D) ²⁰ -9.9° (c. 0.97 H₂ O)

Chiral HPLC analysis of enantiomeric excess was performed on a ChromTechα-acid glycoprotein (α₁ -AGP) column, eluted with 85% 0.1M KH₂ PO₄, 15%CH₃ CN, pH 4.6, in isocratic mode.

For this sample:

ret. time 10.3 min, 99.65% (S)-isomer

ret. time 18.8 min, 0.35% (R)-isomer therefore 99.3% enantiomericexcess.

¹ H NMR (D₂ O, 300 MHz, ref. to HOD, 4.65 ppm): δ7.25 (dt, J=8,1 Hz, 2H)7.17 (t, J=7 Hz,1H) 7.02 (t, J=7 Hz,1H) 6.92 (m, 3H) 6.81 (s, 1H) 6.72(dd, J=8, 2 Hz, 1H) 2.74 (ddt, J=18, 5, 4 Hz, 1H) 2.45 (m, 2H) 1.88-1.62(m, 4H) ppm.

MS (FAB, + ions): m/z 539 (M+K), 501 (M+H), 463 (M-K +2H).

Anal. Calcd. for C₁₆ H₁₆ O₇ PSK₃ +0.75 H₂ O: C, 37.38; H, 3.43; P, 6.02;S, 6.24. Found: C, 37.37; H, 3.44; P, 5.86; S, 6.08

EXAMPLE 176

(R)-(+)-3-Phenoxy-α-phosphonobenzenebutanesulfonic acid, tripotassiumsalt

A.(R)-α-[[(Dimethylamino)thioxomethyl]thio]-3-phenoxybenzenebutanephosphonicacid

To a solution of 0.32 g (0.60 mmol, 1 eq) of Example 175 Part Dα-(R)-isomer in 12 mL of acetonitrile was added 18 mL (18 mmol, 30 eq)of 1N hydrochloric acid. The initially opaque, milky white solutionbecame homogeneous after 2 min and was stirred at RT for 14 h. Thereaction was concentrated and the residue was dissolved in methanol andpassed through a column of Biorad AG-50W-X8 ion exchange resin, H⁺ form(60 mL bed volume, 102 meq) which has been equilibrated with water (50mL), 0.1N HCl (100 mL), water (100 mL pH of eluant ˜7) and 10% methanolin water prior to use. The column was eluted with methanol to afford0.18 g (72%) of title compound as a clear viscous oil.

[α_(spec) ]_(D) ²⁰ -2.3° (c. 2.6, MeOH)

³¹ P NMR (CD₃ OD, 121 MHz, ref. to 10% H₃ PO₄, 0 ppm): 24.2 ppm.

TLC Silica gel (6:3:1 n-propanol:ammonium hydroxide:water): R_(f) 0.56

B. (R)-(+)-3-Phenoxy-α-phosphonobenzenebutanesulfonic acid, tripotassiumsalt

To a solution of 0.18 g (0.59 mmol, 1 eq) of Part A compound in 40 mL of98% formic acid was added 2.16 mL (21.2 mmol, 50 eq) of 30% hydrogenperoxide in water. The reaction became cloudy after 0.5 min and aprecipitate formed after ˜1 min. After 45 min, the reaction wasconcentrated and the residue was dissolved in water. The solution wascooled to 0° C. and the excess peroxide was decomposed by the slowaddition of 25 mL of 1N potassium sulfite. The solution was againconcentrated and the residue was coevaporated twice with water. Theresidue was dissolved in 10 mL of water and the pH of the solution (pH˜3) was brought to pH 12 with 1N potassium hydroxide. The solution wasthen chromatographed on CHP-20P gel (2.5 cm×25 cm) eluting with water.Fractions containing pure product were pooled and concentrated to afforda clear waxy residue which was dissolved in water, filtered andlyophilized to afford 132 mg (56%) of title compound as a whitelyophilate.

TLC Silica gel (6:3:1 n-propanol:ammonium hydroxide:water): R_(f) 0.21.

[α_(spec) ]_(D) ²⁰ +9.5° (c. 0.89 H₂ O)

Chiral HPLC analysis of enantiomeric excess was performed on a ChromTechα-acid glycoprotein (α₁ -AGP) column, eluted with 85% 0.1M KH₂ PO₄, 15%CH₃ CN, pH 4.6 in an isocratic mode.

For this sample:

ret. time 17.8 min, 97.77% (R)-enantiomer

ret. time 10.9 min, 2.23% (S)-enantiomer therefore 95.5% enantiomericexcess.

¹ H NMR (D₂ O, 300 MHz, ref. to HOD, 4.65 ppm): δ7.25 (t, J=8 Hz, 2H)7.17 (t, J=7 Hz, 1H) 7.03 (t, J=7 Hz, 1H) 6.92 (m, 3H) 6.81 (s, 1H) 6.72(dd, J=8, 2 Hz, 1H) 2.72 (ddt, J=18, 5, 4 Hz, 1H) 2.47 (m, 2H) 1.95-1.56(m, 4H) ppm.

IR (KBr): 3412 (br), 3071, 2936, 2866, 1661, 1489, 1204, 1076, 966 cm⁻¹.

MS (FAB, + ions): m/z 539 (M+K), 501 (M+H), 463 (M-K+2H).

Anal. Calcd for C₁₆ H₁₆ O₇ PSK₃ +3.33 H₂ O: C, 34.28; H, 4.07; P, 5.52;S, 5.72 Found: C, 34.28; H, 3.99; P, 5.14; S, 5.79.

EXAMPLE 177

[3aR-[2(R*),3aα, 7aβ]]-[1-[[(Dimethylamino)thioxomethyl]thio]-4-(3-phenoxyphenyl)butyl]octahydro-1,3-dimethyl-2-1H-1,3,2-benzodiazaphosphole,2-oxide

and

[3aR-[2(S*), 3aα,7aβ]]-[1-[[(Dimethylamino)thioxomethyl]thio]-4-(3-phenoxyphenyl)butyl]-octahydro-1,3-dimethyl-2-1H-1,3,2-benzodiazaphosphole,2-oxide

A. [3aR-(3aR,7aβ)]-2-[[[(Dimethylamino)thioxomethyl]thio]]octahydro-1,3-dimethyl-1H-1,3,2-benzodiazaphosphole,2-oxide

To a stirred solution of 502 mg (2.48 mmol) of Example 175 Part Bcompound in 10 mL of THF under argon at -78° C. was added 1.09 mL (2.73mmol) of a 2.5N solution of n-butyllithium in hexanes dropwise over 10minutes. After stirring at -78° C. for one hour, 87 mg (2.73 mmol) ofsulfur was added via a solid addition tube, and temperature of thereaction was raised to -20° C. over 1 hour. The reaction mixture wastreated with 0.93 mL (6.69 mmol) of triethylamine and 276 mg (2.23 mmol)of dimethylthiocarbamoyl chloride at -20° C., stirred for 5 minutes,then allowed to warm to room temperature. The mixture was diluted withether and washed with water. The aqueous layer was back extracted withether and the organics were combined, dried and concentrated to afford558 mg of an oil. The crude product was purified by flash chromatographyon silica gel (50 g) eluted with 96:4 ethyl acetate/methanol. Purefractions were combined and concentrated to yield 337 mg (47%) of titlecompound as a clear oil.

TLC (Silica gel, 9:1 ethyl acetate/methanol) R_(f) =0.35.

MS (CI, + ions) 332 (M+H).

³¹ P NMR (CDCl₃, 121 MHz) 37.7 ppm.

B. 3aR-[2(R*),3aα, 7aβ]]-[1-[[(Dimethylamino)thioxomethyl]thio]-4-(3-phenoxyphenyl)butyl]octahydro-1,3-dimethyl-2-1H-1,3,2-benzodiazaphosphole, 2-oxide

To a stirred solution of 89 mg (0.28 mmol) of Part A compound in 1 mL ofTHF under argon at -78° C. was added 122 μL (0.31 mmol) of a 2.5Nsolution of n-butyllithium in hexanes dropwise over 10 minutes. After 90minutes at -78° C., 0.096 mL (0.55 mmol) of hexamethylphosphoramide wasadded, followed by 98 mg (0.30 mmol) of 3-(3-phenoxyphenyl)propyliodidein 1 mL of THF. After 28 hours at -78° C., the reaction was quenchedwith methanol and allowed to reach room temperature. The mixture wasconcentrated, then dissolved in ether and washed with water and brine,dried over sodium sulfate, and concentrated to afford 129 mg of a yellowoil. The crude product was purified by flash chromatography on silicagel (15 g) eluted with 98:2 ethyl acetate/methanol. Fractions (#11-19)containing pure material were combined and concentrated to yield 50 mg(34%) of title α-(R) isomer as a clear oil.

TLC (Silica gel, 9:1 ethyl acetate/methanol) R_(f) =0.45.

C. [3aR-[2(S*),3aα, 7aβ]]-[1-[[(Dimethylamino)thioxomethyl]thio]-4-(3-phenoxyphenyl)butyl]octahydro-1,3-dimethyl-2-1H-1,3,2-benzodiazaphosphole, 2-oxide

Fractions #21-30 were combined and concentrated to provide 10 mg (7%) oftitle isomer as a clear oil.

TLC (Silica gel, 9:1 ethyl acetate/methanol) R_(f) =0.39.

MS (CI, + ions) 532 (M+H).

³¹ P NMR (CDCl₃, 121 MHz) 39.3 ppm.

The Parts B and C compounds may then be separated and subjected to acidhydrolysis and then oxidation and salt formation as described in Example175 to form the title compound of Examples 175 and 176.

EXAMPLE 178

[3aR-[2(R*),3aα, 7aβ]]-[1-[[(Dimethylamino)thioxomethyl]thio]-4-(3-phenoxyphenyl)butyl]octahydro-1,3-dimethyl-2-1H-1,3,2-benzodiazaphosphole,2-oxide

A. [3aR-(3aα, 7aβ)]-Octahydro-1,3-dimethyl-1H-1,3,2-benzodiazaphosphole,2-oxide

To a stirred solution of 497 mg (3.49 mmol) of Example 175 Part A(R,R)-diamine and 1.07 mL (7,89 mmol) of triethylamine in 25 mL oftetrahydrofuran (THF) under argon at -78° C. was added dropwise over 5minutes 335 μL (3.84 mmol) of phosphorus trichloride. The cloudysolution was allowed to warm to room temperature and was filtered underargon through a pad of celite and magnesium sulfate. The filtrate waschilled to -78° C. under argon and treated with 536 μL of triethylamineand 63 μL (3.49 mmol) of water. The mixture was allowed to warm to roomtemperature and was filtered under argon through a pad of celite andmagnesium sulfate and concentrated to provide 544 mg (82%) of titlecompound as a yellow oil.

³¹ P NMR (CDCl₃, 121 MHz) 6 27.3 ppm.

B. [3aR-[2(R*), 3aα,7aβ)]-Octahydro-1,3-dimethyl-2-[4-(3-phenoxyphenyl)-1-[(trimethylsilyl)oxy]butyl]-1H-1,3,2-benzodiazaphosphole,2-oxide

C. [3aR-[2(S*),3aα,7aβ)]-Octahydro-1,3-dimethyl-2-[4-(3-phenoxyphenyl)-1-[(trimethylsilyl)oxy]butyl]-1H-1,3,2-benzodiazaphosphole,2-oxide

A solution of 544 mg (2.89 mmol) of Part A compound and 534 mg (2.22mmol) of 3-phenoxybenzenebutanal (Example 180 Part B) in 5 mL ofmethylene chloride under argon was treated with 814 μL (3.33 mmol) ofbis[trimethylsilyl) acetamide at room temperature and stirred for 17hours. The reaction was quenched with water and extracted with methylenechloride (3×35 mL). The combined organics were washed with brine, dried(sodium sulfate), and concentrated to provide 875 mg of a yellow oil.The crude product mixture was purified by flash chromatography on silicagel (80 g) eluted with 2 L of 9:1 hexane/acetone followed by 2 L of85:15 hexane/acetone and 1.5 L of 8:2 hexane/acetone. Fractionscontaining the more polar α-(R) isomer (title B) were combined andconcentrated to yield 135 mg (14%) of title B compound as a clear oil.

TLC Silica gel (1:1 hexane/acetone) R_(f) =0.29.

³¹ P NMR (CDCl₃, 121 MHz) δ41.1 ppm.

Fractions #85-96 were combined and concentrated to yield 112 mg (12%) ofthe pure Part C α-(S)isomer.

TLC Silica gel (1:1 hexane/acetone) R_(f) =0.31.

³¹ P NMR (CDCl₃, 121 MHz) δ27.3 ppm.

D. [3aR-[2(R*), 3aα,7aβ)]-Octahydro-2-[1-hydroxy-4-(3-phenoxyphenyl)butyl]-2,3-dimethyl-1H-1,3,2-benzodiazaphosphole,2-oxide

To a stirred solution of 125 mg (0.20 mmol) of Part B isomer in 1 mL ofTHF was added 0.29 mL (0.29 mmol) of a 1.0N solution oftetrabutylammonium fluoride in THF. After stirring for three hours atroom temperature, the mixture was diluted with ether, washed withsaturated sodium bicarbonate, brine, dried (sodium sulfate), andconcentrated to provide 104 mg of a white solid. The crude product waspurified by flash chromatography on silica gel (15 g) eluted with97.5:2.5 ethyl acetate/methanol. Clean fractions (#41-71) were combinedand concentrated to yield 100 mg (93%) of title compound as a whitesolid. m.p. 122°-125° C.

TLC Silica gel (1:1hexane/acetone) R_(f) =0.44.

³¹ P NMR (CDCl₃, 121 MHz) δ41.1 ppm.

E. [3aR-[2(R*), 3aα, 7β]]-[1-[[(Dimethylamino)thioxomethyl]thio]-4-(3-phenoxyphenyl)butyl]octahydro-1,3-dimethyl-2-1H-1,3,2-benzodiazaphosphole, 2-oxide

To a stirred suspension of 56 mg (0.13 mmol) of Part D compound, 30 mg(0.09 mmol) of dimethyldithiocarbamic acid, zinc salt, and 47 mg (0.18mmol) of triphenylphosphine in 1 mL of THF at 0° C. under argon wasadded a solution of 52 μL (0.27 mmol) of diisopropyl azodicarboxylate in0.5 mL of THF over fifteen minutes. The reaction was stirred at roomtemperature for 45 hours, then diluted with ether and quenched withwater. The organics were washed with brine, dried (sodium sulfate), andconcentrated to provide 150 mg of an oil. The crude product was purifiedby flash chromatography on silica gel (15 g) eluded with ethyl acetate.Pure fractions were combined and concentrated to yield 15 mg (21%) oftitle compound as a film, the α(R)-isomer.

TLC Silica gel (1:1 hexane/acetone) R_(f) =0.20. Note: This is identicalto Example 175 Part D compound and is the precursor to the Example 176compound.

MS (C.I, + ions) 532 (M+H).

³¹ P NMR (CDCl₃, 121 MHz) δ41.2 ppm.

EXAMPLE 179

(S)-(-)-3-Phenoxy-α-phosphonobenzenebutanesulfonic acid, tripotassiumsalt

A. [3aR-(3aα,7aβ)]-2-Chlorooctahydro-1,3-dimethyl-1H-1,3,2-benzodiazaphosphole,2-oxide

A solution of 4.72 g (33.20 mmol) of Example 175 Part A diamine and12.63 g (125.0 mmol) of triethylamine in 50 mL of toluene at 0° C. wastreated with 5.00 g (33.20 mmol) of phosphorus oxychloride dropwise over15 min. The reaction mixture was stirred for 10 min. at 0° C. and warmedto RT. After 3 h the solids were filtered off and the filtrateconcentrated to a slurry. The slurry was purified by flashchromatography (100 g of silica gel) eluting with 15:85 acetone/tolueneto provide 6.50 g (88%) of title chloride as a low melting solid.

TLC Silica gel (1:4 acetone/toluene) R_(f) =0.30.

¹ H NMR (CDCl₃, 300 MHz): δ2.85 (td, 1H, J=10.8, 3.0 Hz) 2.67 (d, 3H,J=10.0 Hz) 2.55 (d+m, 4H, J=18.0 Hz) 2.05 (m, 2H) 1.85 (m, 2H) 1.35 (m,4H) ppm.

¹³ C NMR (CDCl₃, 75.6 MHz): δ63.5 (d, J=7.0 Hz) 62.5 (d, J=10.0 Hz) 28.027.5 (d, J=7.0 Hz) 27.0 (d, J=7.0 Hz) 24.0 23.9 ppm.

³¹ P NMR (CDCl₃, 121.7 MHz): δ36.6 ppm

B. [3aR-(3aα,7aβ)]-Octahydro-1,3-dimethyl-1H-1,3,2-benzodiazaphosphole-2-methanesulfonicacid, ethyl ester, 2-oxide

To a rapidly stirred solution of 6.20 g (50.0 mmol) of ethylmethanesulfonate in 150 mL of THF at -73 ° C. (internal temperature) wasadded 20 mL (50 mmol) of 2.5M n-butyllithium dropwise over 20 min (Theinternal temperature was not allowed to rise above -69° C. throughoutthe addition of n-BuLi). After an additional 30 min., 5.56 g (25.0 mmol)of freshly prepared Part A chloride in 25 mL of THF was added at a rateto keep the solution temperature below -69° C. The reaction mixture wasstirred for 0.3 h at -73° C. and for 3 h at -30° C. The reaction mixturewas poured into 250 mL of a rapidly stirring mixture of 1:1 saturatedaqueous NaHCO₃ solution/ethyl acetate. The mixture was partitionedbetween ethyl acetate and water (3×75 mL). The organic extracts weredried (Na₂ SO₄) and concentrated to an oil. The oil was purified byflash chromatography (200 g silica gel ) eluting with methylene chloride(600 mL) followed by 93:7 dichloromethane/isopropanol (1000 mL) toprovide 6.60 g (85%) of title compound as a low melting solid.

TLC Silica gel (1:9 2-propanol/dichloromethane) R_(f) =0.58.

IR (KBr) 2947, 2878, 1478, 1451, 1348, 1258, 1236, 1215, 1165, 1123,1026, 1005, 918 cm⁻¹.

Mass Spec (CI--NH₃, + ions) m/e 638 (2M+NH₄), 621 (2M+H), 328 (M+NH₄),311 (M+H).

Anal. Calc'd for C₁₁ H₂₃ N₂ O₄ PS: C, 42.57; H, 7.47; N, 9.03; P, 9.89;S, 10.33 Found: C, 42.95; H, 7.55; N, 9.10; P, 9.81; S, 10.59.

[α]_(D) ²⁰ =-79° CHCl₃, (c=1)

¹ H NMR (CDCl₃, 300 MHz): δ4.35 (q, 2H, J=6.9 Hz) 3.82 (t, 1H, J=14.1Hz) 3.73 (t, 1H, J=15.0 Hz) 2.93 (td, 1H, J=9.0, 2.0 Hz) 2.80 (td, 1H,J=9.0, 2.0 Hz) 2.67 (d, 3H, J=8.0 Hz) 2.63 (d, 3H, J=8.0 Hz) 2.05 (m,2H) 1.85 (m, 2H) 1.40 (t, 3H, J=7.0 Hz) 1.30 (m, 4H) ppm.

¹³ C NMR (CDCl₃, 75.6 MHz): δ67.0 64.3 (d, J=6.8 Hz) 62.8 (d, J=9.0 Hz)46.3 (d, J=102.0 Hz) 28.7 (d, J=2.0 Hz) 27.8 (d, J=10.5 Hz) 27.7 (d,J=8.3 Hz) 27.4 (d, J=4.5 Hz) 24.0 23.9 ppm.

³¹ P NMR (CDCl₃, 121.7 MHz): δ26.7 ppm

C. [3aR-(3aα,7aβ)]-Octahydro-1,3-dimethyl-1H-1,3,2-benzodiazaphosphole-2-methanesulfonicacid, tetrabutylammonium salt, 2-oxide

A suspension of 5.00 g (16.12 mmol) of Part B compound and 6.02 g (16.29mmol) of tetrabutylammonium iodide in 30 mL of anhydrous THF at RT wasstirred for 10 min. at 0° C. and warmed to RT. After 30 h the clearsolution was concentrated to a thick oil. The oil was dried under vacuum(0.009 mm Hg) overnight. The honey-like oil was used without furtherpurification.

¹ H NMR (CD₃ OD, 300 MHz): δ3.55 (t, 1H, J=14.1 Hz) 3.50 (t, 1H, J=14.1Hz) 3.30 (m, 8H) 3.00 (m, 1H) 2.67 (m, 1H) 2.62 (d, 3H, J=10.0 Hz) 2.58(d, 3H, J=10.0 Hz) 2.05 (t_(br), 2H, J=10.0 Hz) 1.85 (m, 2H) 1.70 (m,8H) 1.40 (m, 12H) 1.05 (t, 12H, J=8.0 Hz) ppm.

¹³ C NMR (CDCl₃, 75.6 MHz): δ64.1 (d, J=6 Hz) 63.0 (d, J=6.8 Hz) 58.648.4 (d, J=107 Hz) 29.0 (d, J=2.0 Hz) 28.9 (d, J=4.5 Hz) 27.9 (d, J=10Hz) 24.2 (d, J=18 Hz) 24.0 23.9 19.6 13.6 ppm.

³¹ P NMR (CD₃ OD, 121.7 MHz): δ35.4 ppm

Mass Spec (FAB, + ions) m/e 242 (Bu₄ N).

Mass Spec (high res., FAB, - ions)

Calcd for C₉ H₁₈ O₄ N₂ PS: 281.0725 Found: 281.0717

[α]_(D) ²⁰ =-33.8° CH₃ OH (c=1)

D. (S)-(-)-3-Phenoxy-α-phosphonobenzenebutanesulfonic acid, tripotassiumsalt

To a slurry of 3.29 g (6.29 mmol) of Part C compound in 20 mL of dry THFat -90° C. (internal temperature) under argon was added 3.0 mL (7.50mmol) of 2.5M n-BuLi in hexanes to give a yellow solution. After 0.5 hat -90° C. the solution was treated with 2.10 g (6.29 mmol) of3-(3-phenoxyphenyl)propyl iodide in 6 mL of THF at such at rate to keepthe internal temperature below -85° C. The reaction mixture was stirredat -90° C. for 3 h when it was gradually warmed to -74° C. overnight.The mixture was quenched with 360 uL of acetic acid in 3 mL of THF andallowed to warm to RT. The mixture was concentrated and acidified with12 mL of 2M HCl solution (24 mmol). The reaction mass was extracted withhexane, the aqueous layer was heated to 80° C. for 3 hours and thendiluted with 2-propanol until a clear solution resulted. After heatingan additional hour the solvent was evaporated and the residue pumped(=0.5 mm pressure) for 0.5 h. The remainder was dissolved in 30 mL (30mmol) of 1M KOH solution and freeze dried to provide a cream coloredsolid. The solid was diluted with water and eluted through 24 g ofAG50X8 (63 meq, K⁺ form) ion exchange resin. Final purification wasaccomplished by MPLC on a column of CHP20P gel (125 mL) eluting withwater (200 mL) followed by a gradient created by the gradual addition of500 mL of acetonitrile to a reservoir of 500 mL of water. Approximately10 mL fractions were collected. Pure fractions were pooled, theacetonitrile was removed under reduced pressure and the aqueous solutionlyophilized to provide 1.48 g (47%) of title compound as a whitelyophilate.

TLC Silica gel (6:3:1 propanol/ammonium hydroxide/water) R_(f) =0.2

Chiral HPLC analysis of enantiomeric excess was performed on a ChromTechα-acid glycoprotein (α1-AGP) column: isocratic 85% 0.1M KH₂ PO₄ /15% CH₃CN, (pH 4.6) in isocratic mode.

For this sample title compound (S)-isomer: retention time ≈10.3 min. 94%

Example 176 compound (R)-isomer: retention time ≈19.0 min. 6%

Therefore, the enaniomeric excess is 88%.

Anal. Calc'd for C₁₆ H₁₆ O₇ PSK₃ +2.2 H₂ O: C, 35.54; H, 3.81; P, 5.73;S, 5.93 Found: C, 35.54; H, 3.98; P, 5.42; S, 6.30.

EXAMPLE 180

(R)-(+)-3-Phenoxy-α-phosphonobenzenebutanesulfonic acid, tripotassiumsalt

A. 4-(3-Phenoxyphenyl)butyl alcohol

A (1) 3-Phenoxybenzyl alcohol

Sodium borohydride (961 mg, 25.3 mmol) was added in one portion to asolution of 3-phenoxybenzaldehyde (10.0 g, 50.5 mmol) in methanol (150mL) at RT under argon. Once the bubbling ceased, the reaction wasstirred at RT for 5 min, then adjusted to pH 6 with glacial acetic acid(about 1 mL). The reaction was concentrated in vacuo to give a residue,which was partitioned between EtOAc (200 mL) and saturated NaHCO₃ (50mL). The organic layer was washed with water and brine (50 mL each),then dried over MgSO₄. Evaporation gave title compound (10.1 g, 100%) asa tan oil.

A (2) 3-Phenoxybenzylbromide

Phosphorus tribromide solution (11.0 mL, 1M in CH₂ Cl₂, 11.0 mmol) wasadded over 5 min to a solution of Part 1(A) alcohol (2.00 g, 10.0 mmol)in CH₂ Cl₂ (30 mL) under argon at RT. The yellow reaction was stirred atRT for 10 min, diluted with CH₂ Cl₂ (100 mL), and washed with saturatedNaHCO₃ (2×30 mL). The organic layer was dried over MgSO₄. Evaporationgave a pale yellow oil, which was purified by flash chromatography onsilica gel (75 g) eluting with 10:90 CH₂ Cl₂ /hexane to provide titlebromide (1.57 g, 60% ) as a yellow oil.

A (3) 4-(3-Phenoxyphenylbutyl alcohol

A Grignard solution of ClMg (CH₂)₃ OMgCl (19.2 mL, 0.6M in THF, 11.5mmol) was added to a mixture of Part A(2) bromide (1.51 g, 5.74 mmol)and copper(I) iodide (11 mg, 0.057 mmol) in THF (10 mL) at 0° C. underargon over a period of 5 min. The dark green reaction was stirred at 0°C. for 30 min, then quenched by dropwise addition of 2-propanol (2 mL).The reaction was diluted with diethyl ether (100 mL) and washed with 1NKHSO₄ (2×50 mL). The aqueous layers were back-extracted with diethylether (20 mL). The combined organic layers were dried over MgSO₄.Evaporation gave a pale yellow oil, which was purified by flashchromotography on silica gel (100 g) eluting with 30:70 EtOAc/hexane toprovide title alcohol (1.10 g, 79%) as a colorless oil.

B. 3-Phenoxybenzenebutanal

To a stirred solution of 3.4 mL (48.6 mmol) of methyl sulfoxide in 50 mLof CH₂ Cl₂ under argon at -78° C. was added 3.9 mL (44.5 mmol) of oxalylchloride dropwise over 5 min. The reaction was stirred at -78° C. for0.5 h at which time 9.8 g (40.4 mmol) of Part A alcohol in 15 mL of CH₂Cl₂ was added dropwise. The reaction was stirred at -78° C. for 20 min,warmed to -30° C. for 5 min, cooled back down to -78° C. and treatedwith 22.6 mL (162 mmol) of triethylamine. The reaction gradually warmedto -20° C. and was quenched with 150 mL of water. The mixture wasdiluted with a 1:1 mixture of hexanes/ethyl acetate and the layers wereseparated. The organics were dried over Na₂ SO₄ and evaporated todryness to provide 8.8 g (91% ) of title compound as a pale yellow oil.

TLC Silica gel (70:30 hexanes/ethyl acetate) R_(f) =0.40.

C. 4,6-Dimethyl-2-[3-(3-phenoxyphenyl)propyl]-1,3-dioxane

To a solution of 5.6 g (23.33 mmol) of Part B aldehyde in 25 mL ofbenzene was added 2.4 g (23.33 mmol) of (2S, 4S)-(+)-pentanediol and a50 mg (0.36 mol) of p-toluenesulfonic acid. The reaction was refluxedfor 2 h using a Dean-Stark trap for the azeotropic removal of water. Thereaction was diluted with ethyl acetate, washed with sat. NaHCO₃solution, water, dried over MgSO₄ and evaporated to provide a crudeyellow oil. Flash chromatography was performed on 300 g of silica geleluting with 90:10 hexanes/ethyl acetate. Pure product fractions werecombined and evaporated to provide 5.5 g (72%) of title compound as acolorless oil.

TLC Silica gel (90:10 hexanes/ethyl acetate) R_(f) =0.21.

[α]_(D) ²⁰ -13.1° (c=1, CH₂ Cl₂)

MS (CI--NH₃, + ions) m/e 344 (M+NH₄), 326 (M).

D.[R-[R*[R*(R*)]]]-α-(3-Hydroxy-1-methylbutoxy)-3-phenoxybenzenebutanephosphonicacid, diethyl ester

(Yokomatsu, T., Shibuya, S., Tetrahedron Asymmetry 1992, 3, 377-8).

To a solution of 2.9 mL (16.87 mmol) of triethyl phosphite in 7 mL ofCH₂ Cl₂ at -78° C. under argon was added dropwise 1.5 mL (13.50 mmol) oftitanium (IV) chloride. The resulting orange solution was stirred at-78° C. for 0.5 h at which time 2.2 g (6.75 mmol) of Part C compound in5 mL of CH₂ Cl₂ was added dropwise over 0.5 h (internal temperature ofthe reaction maintained at -68° C.). The reaction was stirred for 48 hat -78° C. at which time the reaction was poured into 200 mL of a 1:1mixture of NaHCO₃ /ethyl acetate and extracted. The organics were washedwith water, brine, dried (MgSO₄) and evaporated to provide 2.0 g of acrude oil. Flash chromatography was performed on 200 g of silica geleluting with 4:1 dichloromethane/acetone. Pure product fractions werepooled and evaporated to provide 1.5 g (48%) of title compound as acolorless oil.

TLC Silica gel (4:1 dichloromethane/acetone) R_(f) =0.24.

[α]_(D) ²⁰ +15.8 (c=1 CH₂ Cl₂)

IR (Film, CH₂ Cl₂) 3410, 3040, 2969, 2870, 1584, 1487, 1447, 1385, 1250,1215, 1163, 1047 cm⁻¹.

³¹ P NMR (CDCl₃, 121 MHz, ref. to 10% H₃ PO₄, 0 ppm): 24.20 ppm.

HRMS (EI, + ions) m/z Calculated for C₂₅ H₃₇ O₆ P: M⁺ 464.2328 Found:464.2316

E. (R)-α-Hydroxy-3-phenoxybenzenebutanephosonic acid, diethyl ester

To a solution of 3 mL (6.00 mmol) of 2.0M oxalyl chloride in CH₂ Cl₂ in3.5 mL of CH₂ Cl₂, under argon at -70° C., was added dropwise 535 μL(7.54 mmol) of DMSO (exothermic). This mixture was stirred at -70° C.for 15 min at which time 1.4 g (3.02 mmol) of Part D compound in 5 mL ofCH₂ Cl₂ was added dropwise. The reaction was stirred at -70° C. for 1 h,treated with 1.7 mL of triethylamine and allowed to warm to RT. Thereaction was quenched with water and diluted with a 1:1 mixture ofhexanes/ethyl acetate. The organics were dried (MgSO₄) and evaporated toprovide 1.4 g of a crude oil. The crude oil was treated with 14 mL ofdioxane, 70 mg (0.37 mmol, 5%) of p-toluenesulfonic acid, 1.4 mL ofwater and refluxed for 0.5 h then cooled to RT. The mixture was dilutedwith a 1:1 mixture of water/NaHCO₃ and extracted 3 times with CH₂ Cl₂.The organics were dried (MgSO₄) and evaporated to provide 1.2 g of apale yellow oil. Flash chromatography was performed on 100 g of silicagel eluding with 4:1 dichloromethane/acetone. Pure product fractionswere combined and evaporated to provide 690 mg (60%) of title compoundas a colorless oil.

[α]_(D) ²⁰ -5.9° (c=1, CHCl₃)

TLC Silica gel (4:1 dichloromethane/acetone) R_(f) =0.23.

IR (Film, CH₂ Cl₂) 3306, 2982, 1584, 1485, 1445, 1385, 1250, 1215, 1163,1142, 1096, 1051, 1026, 966 cm⁻¹.

¹ H (300 MHz, CDCl₃): δ7.30-6.70 (m, 9H) 4.15 (m, 4H) 3.95 (m, 1H) 3.87(m, 1H) 2.61 (m, 2H) 1.95 (m, 1H) 1.70 (m, 3H) 1.30 (t, 6H, J=7.1 Hz)ppm.

¹³ C NMR (75 MHz, CDCl₃) δ157.2, 157.0, 144.1, 129.6, 129.4, 123.3,122.9, 118.9, 118.6, 116.2, 67.5 (d, J=161 Hz), 62.6 (d, J=6.8 Hz), 62.4(d, J=6.8 Hz), 35.2, 30.8, 27.2 (d, J=12.8 Hz), 16.4 (d, J=4.5 Hz) ppm.

³¹ P NMR (121 MHz, CDCl₃, ref. to 10% H₃ PO₄, 0 ppm): 25.28 ppm.

HRMS (FAB, + ions) m/z Calculated for C₂₀ H₂₈ O₅ P: (M+H)⁺ =379.1675FOUND: 379.1692

Anal. Calcd. for C₂₀ H₂₇ PO₅ +0.50 mol H₂ O. Effective MW=387.40. C,62.00; H, 7.28; P, 7.99 Found: C, 62.00; H, 7.05; P, 8.13.

F.(R)-α-[[(Dimethylamino)thioxomethyl]thio]-3-phenoxybenzenebutaneohosphonicacid

To a stirred slurry of 415 mg (1.10 mmol) of Part E compound, 585 mg(2.23 mmol) of triphenylphosphine and 252 mg (0.82 mmol) ofdimethyldithiocarbamic acid, zinc salt, in 3 mL of THF at 0° C. underargon was added 446 mg (2.21 mmol) of diisopropyl diazodicarboxylate in2 mL of THF over the course of 20 minutes. The resulting light yellowsolution was allowed to warm to room temperature and stirred for 16hours. The reaction mixture was then evaporated and immediately purifiedby flash chromatography (5×15 cm column, eluting with 1:3ether/dichloromethane). Fractions containing both the product and animpurity were collected, concentrated and re-chromatographed (5×15 cmcolumn, 85:15 ethyl acetate/hexane). The resulting yellow oil stillcontained ca. 8-10% of diisopropyl dicarbazide as an impurity. The yieldof title compound was 490 mg (82% of 91% pure material).

[α]_(D) ²⁰ =24.5° (c=0.99, CHCl₃)

G. (R)-(+)-3-Phenoxy-α-phosphonobenzenebutanesulfonic acid, tripotassiumsalt

To a stirred solution of 410 mg (0.851 mmol) of Part F compound in 3 mLof CH₂ Cl₂ at room temperature under argon was added 0.7 mL (5.3 mmol)of bromotrimethylsilane. The nearly colorless solution was stirred for16 hours and then evaporated at less than 25° C. The residue wasdissolved in 10 mL of dry methanol and stirred for 1 hour.Re-evaporation gave 358 mg (99%) of the diacid as a colorless glass.

To a solution of 0.326 g (0.77 mmol, 1 eq) of the diacid in 50 mL of 98%formic acid was added 4.2 mL (38 mmol, 50 eq) of 30% hydrogen peroxidein water. The reaction became cloudy after 0.5 min and a precipitateformed after ˜2 min. After 1 h, the reaction was cooled to 0° C. and theexcess peroxide was decomposed by the slow addition of 40 mL of 1Npotassium sulfite. The solution was concentrated and the residue wascoevaporated twice with water. The residue was dissolved in 10 mL ofwater and the pH of the solution (pH ˜3) was brought to pH 12 with 1Npotassium hydroxide. The solution was then chromatographed on CHP-20Pgel (2.5 cm×25 cm) eluting with water. Fractions containing product wereanalyzed by HPLC, then pooled and concentrated to afford a clear waxyresidue which was dissolved in water, filtered and lyophilized to afford201 mg (48%) of title compound.

TLC Silica gel (6:3:1 n-propanol:ammonium hydroxide:water): R_(f) 0.21.

Chiral HPLC analysis of enantiomeric excess was performed on a ChromTechα-acid glycoprotein (α₁ -AGP) column, eluted with 85% 0.1M KH₂ PO₄, 15%CH₃ CN, pH 4.6 in isocratic mode.

For title compound: ret. time 18.5 min, 98.95% (R)-enantiomer ret. time11.2 min, 1.05% (S)-enantiomer therefore 97.9% enantiomeric excess ofthe (R)-isomer.

Anal. Calc'd for C₁₆ H₁₆ O₇ PSK₃ +2.5 H₂ O: C, 35.19; H, 3.88; P, 5.67;S, 5.87 Found: C, 35.19; H, 3.54; P, 5.32; S, 6.27.

EXAMPLE 181

(S)-(-)-3-Phenoxy-α-phosphonobenzenebutanesulfonic acid,1-adamantanamine (1:2) salt

A sample of the (R)-(-)-trisalt (94:6, (S):(R)) prepared in Example 179(70 mg, 0.14 mmol) was stirred with 3 g of Ag50-X8 ion exchange resin(7.5 meq, H* form) for 1 h in 5 mL of water and 3 mL of methanol. Themixture was slowly eluted through an additional column of Ag50-X8 ionexchange resin (1 g, 2.5 meq, H⁺ form) with 1:1 methanol/water.Approximately 3 mL fractions were collected. Fractions #2 to 7 werepooled, the methanol was removed under reduced pressure and the aqueoussolution lyophilized to provide 54 mg (100%) of the free acid form ofthe title salt as a thin film.

The free acid (54 mg, 0.14 mmol) in 3 mL of a 1:1 methanol/watersolution was treated with 39 mg (0.28 mmol, 2 eq) of adamantanamine andthe mixture stirred for 0.5 h. The mixture was concentrated to a whitesolid. The solid was recystallized from hot water and 2-propanol. Thewhite granules were collected to yield 79 mg (85 %) of title salt as a97:3 mixture of (S):(R) enantiomers. The recrystallization procedure wasrepeated to provide 66 mg (85 %) of title salt, as a white solid, mp248°-252° C. The two recystalizations from hot 2-propanol/water improvedthe ratio of (S):(R) enantiomers from 94:6 to 98:2 determined by HPLC asdescribed on the α-acid glycoprotein column.

TLC Silica gel (6:3:1 n-propanol/conc. ammonia/water) R_(f) =0.30.

IR (KBr) 3426, 3086, 3065, 3036, 2915, 2855, 1609, 1582, 1485, 1233,1215, 1175, 1022, 882 cm⁻¹.

¹ H NMR (CD₃ OD, 400 MHz): δ7.30 (t, 2H, J=8.1 Hz) 7.20 (t, 1H, J=8.0Hz) 7.07 (t, 1H, J=6.2 Hz) 6.95 (m, 3H) 6.86 (s, 1H) 6.73 (dd, 1H,J=8.5, 2.5 Hz) 3.05 (dt, 1H, J=18.0, 6.2 Hz) 2.65 (m, 2H) 2.15 (s+m, 8H)2.00 (m, 2H) 1.90 (s, 12H) 1.75 (d, 6H, J=12.0 Hz) 1.68 (d, 6H, J=12.0Hz) ppm.

Mass Spec (FAB, + ions) m/e 689 (M+H); (FAB, - ions) m/e 385 (M-2 (C₉H₁₇ N)+H).

Anal. Calc'd for C₃₆ H₅₃ O₇ N₂ PS+1.00 H₂ O: C, 61.17; H, 7.84; N, 3.96;P, 4.38; S, 4.54. Found: C, 61.26; H, 7.90; N, 4.00; P, 4.27; S, 4.74.

Regeneration of Metal Salt

Title salt (60 mg, 0.08 mmol) was stirred with 1.5 mL of Ag50-X8 ionexchange resin (2.5 meq, K⁺ form) for 2 h in 3 mL of water and 1 mL ofmethanol (pH=7). The mixture was slowly eluted through an additionalcolumn of Ag50-X8 ion exchange resin (1.5 mL, 2.5 meq, K⁺ form) with 1:1methanol/water. Product containing fractions were pooled, the methanolwas removed under reduced pressure and the aqueous solution lyophilizedto provide 38 mg (95 %) of the tripotassium salt as a white lyophilate.

Chiral HPLC analyis of enantiomeric excess was performed on a ChromTechα-acid glycoprotein (α1-AGP) column eluted with isocratic 85% 0.1M KH₂PO₄, 15% CH₃ CN, pH 4.6.

For this sample,

Example 181 (S)-isomer: retention time ≈9.5 min. 98%

Example 180 (R)-isomer: retention time ≈19.0 min. 2%, therefore a 96%enantiomeric excess of the (S)-isomer.

EXAMPLE 182

(S)-(-)-3-Phenoxy-α-phosphonobenzenebutanesulfonic acid,(S)-α-methylbenzylamine (1:2) salt

A sample of the (-)-isomer (Example 175) (70 mg, 0.14 mmol) was stirredwith 3 g of Ag50-X8 ion exchange resin (7.5 meq, H⁺ form) for 1 h in 5mL of water and 3 mL of methanol. The mixture was slowly eluted throughan additional column of Ag50-X8 ion exchange resin (1 g, 2.5 meq, H+form) with 1:1 methanol/water. Approximately 3 mL fractions werecollected. Fractions #2 to 7 were pooled, the methanol was removed underreduced pressure and the aqueous solution lyophilized to provide 54 mg(100%) of the free acid form of the title salt as a thin film. The freeacid was used without further characterization.

The free acid in 3 mL of a 1:1 methanol/water solution was treated with36 uL (0.21 mmol, 2 eq) of (S)-(-)-α-methylbenzylamine under argon. Themixture was stirred for 0.5 h and concentrated to an oil.Recrystallization from 3 mL of hot acetonitrile and 3 drops of waterfollowed by slow evaporation to dryness provided 60 mg (73%) of titlediamine salt as needles. mp 160°-163° C.

[α]_(D) ²⁰ =-8.0° (methanol, c=1)

IR (KBr) 3447, 3050, 3038, 2938, 2762, 1613, 1582, 1566, 1489, 1242,1213, 1182, 1163, 1072, 1044, 1022, 924, 702 cm⁻¹.

Mass Spec (FAB, + ions) m/e 629 (M+H); (FAB, - ions) m/e 385 (M-2(C₈ H₁₁N)+H).

¹ H NMR (3:1 DMSO:CD₃ OD, 300 MHz): δ7.58-7.30 (m, 12H) 7.25 (t, 1H,J=8.0 Hz) 7.10 (t, 1H, J=8.0 Hz) 7.00 (d, 3H, J=9.0 Hz) 6.85 (m, 1H)6.75 (dd, 1H, J=7.0, 2.0 Hz) 4.40 (q, 2H, J=6.5 Hz) 2.80 (dt, 1H,J=19.0, 5.8 Hz) 2.57 (m, 2H) 1.80 (m, 4H) 1.55 (d, 6H, J=6.5 Hz) ppm.

The needles were subjected to X-ray crystallographic studies, whichdemonstrated that the (-)-isomer had the (S)-stereochemistry at theα-carbon.

EXAMPLE 183

(S)-α-[Bis[(2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]-3-phenoxybenzenebutanesulfonicacid, monopotassium salt

A. (S)-3-Phenoxy-α-phosphonobenzenebutanesulfonic acid, trisilver salt

A solution of Example 175 product (1.66 g, 3.32 mmol) in water (17 mL)was added over 30 min via syringe pump to a vigorously stirred solutionof silver nitrate (2.02 g, 11.9 mmol) in water (17 mL) under argon at RTin the dark. A white precipitate resulted immediately upon addition.Following addition, additional water (5 mL) was added to aid stirring,and the thick slurry was stirred vigorously at RT for 15 min thenfiltered through a porosity D (10-20 μm) glass fritted funnel. The solidwas washed with water (2×40 mL) and diethyl ether (2×40 mL) thenair-dried for 15 min. The product was further dried by pumping underhigh vacuum in the dark overnight to give title compound (2.28 g, 97%)as a beige solid.

B.(S)-α-[Bis[(2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]-3-phenoxybenzenebutanesulfonicacid, monopotassium salt

A suspension of Part A compound (2.12 g, 3.00 mmol) and activated 4Amolecular sieves (2.1 g) in CH₂ Cl₂ (25 mL) was stirred at RT in thedark under argon for 45 min. Anhydrous anisole (1.6 mL, 15.0 mmol) wasadded and the reaction was placed in a 20° C. water bath. To thesuspension was added a solution of 2,2-dimethylpropanoic acid,iodomethyl ester (2.18 g, 9.00 mmol) in CH₂ Cl₂ (5 mL) dropwise slowlyover 15 min via syringe pump ensuring that the reaction temperatureremained below 30° C. The reaction turned bright yellow during addition.The heterogeneous reaction was stirred vigorously at RT in the dark for40 min, then filtered through Celite with the aid of CH₂ Cl₂ (200 mL).Evaporation of the filtrate gave 3.3 g of the crude triesterα-[bis[(2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]-3-phenoxybenzenebutanesulfonicacid, (2,2-dimethyl-1-oxopropoxy)methyl ester as a yellow liquid.

The crude triester was dissolved in CH₃ CN/water (4:1, 40 mL) to give anopaque solution containing a small amount of yellow precipitate. Thereaction was stirred at RT and progress of the solvolysis was monitoredby ¹ H NMR (disappearance of the t-BuCO₂ CH₂ -- sulfonate signal at 5.8ppm [in d₆ -DMSO]). When no sulfonate ester remained (8 h) the reactionwas partitioned between EtOAc (150 mL) and saturated KCl (20 mL). Theresultant biphasic mixture was filtered to remove she yellowprecipitate. The-organic layer was washed with 1M potassium phosphate(pH=6.0, 2×20 mL) and saturated KCl (5 mL), then dried over anhydrousKCl. Evaporation followed by pumping under high vacuum for 1.5 h gave2.0 g of a colorless oil.

CHP20P gel was stirred with 0.5M potassium phosphate buffer (pH=5.0,1000 mL) for 4 h, then packed (5×25 cm column) and flushed with water(500 mL). The column was equilibrated with 5:95 CH₃ CN/water (1.5 L).

The crude product was dissolved in CH₃ CN (5 mL), then water (10 mL) wasadded. The solution was adjusted to pH 5.0 with 1M potassium phosphatebuffer (pH=7.0). The product solution was chromatographed on CHP20P gelprepared above (25 mL fractions), eluted with 5:95 CH₃ CN/H₂ O (250 mL)followed by a gradient created by the gradual addition of 80:20 CH₃CN/H₂ O (1200 mL) to a reservoir of 5:95 CH₃ CN/H₂ O (1200 mL)).Fractions 55-62 were combined and concentrated to a volume of 100 mLconsisting almost entirely of water. The aqueous solution (pH=3.2) wasadjusted slowly to pH=5.0 with 1M potassium phosphate (pH=7.0), thenconcentrated to dryness. The resultant residue was dissolved in CH₃CN/H₂ O (1:4, 10 mL) and lyophilized to give title compound (1.12 g,57%) as a white lyophilate.

TLC (silica gel) (10:90 MeOH/CH₂ Cl₂) R_(f) 0.25

Chiral purity was determined by HPLC on a Chrom Tech α-acid glycoproteincolumn, with isocratic elution of 10 mM KH₂ PO₄ /iPrOH/MeOH buffer(78:16:6). This sample was 99.2% (S)-isomer (retention time=23.5 min)and 0.8% (R)-isomer (retention time=17.0 min) and therefore had a 98.4%enantiomeric excess favoring the (S)-isomer.

IR (KBr) 2974, 1755, 1584, 1485, 1250, 1215, 1140, 1024, 1003, 963 cm⁻¹.

MS (FAB, + ions) 653 (M+H), 691 (M+K)

Anal. Calcd. for C₂₈ H₃₈ KO₁₁ PS+0.60 KH₂ PO₄ : C, 45.69; H, 5.38; P,6.75 Found: C, 45.64; H, 5.43; P, 7.12.

¹ H NMR (300 MHz, DMSO): δ7.38 (t, 2H, J=8.0 Hz) 7.27 (t, 1H, J=7.8 Hz)7.12 (t, 1H, J=7.4 Hz) 7.00 (d, 2H, J=7.7 Hz) 6.96 (d, 1H, J=7.9 Hz)6.83 (t, 1H, J=1.8 Hz) 6.78 (dd, 1H, J=2.2 Hz, 7.8 Hz) 5.56 (m, 4H) 3.03(dt, 1H, J=5.6 Hz, 19.5 Hz) 2.50 (m, 2H, buried under DMSO signal)2.02-1.70 (m, 4H) 1.15 (s, 9H) 1.13 (s, 9H) ppm.

¹ P NMR (122 MHz, 5:3 DMSO/D₂ O): δ23.45 0.07 (KH₂ PO₄) ppm.

The compounds of Examples 42, 93,174, 175 and 183 are particularlypreferred.

What is claimed is:
 1. A method for forming an enantiomer of aphosphonosulfonate compound having the structure ##STR122## wherein R²is OR⁵,R³ and R⁵ represents an alkali metal ion; R⁴ is an alkali metalion; R¹ is a lipophilic group containing at least 7 carbons; Z is H,halogen, lower alkyl or lower alkenyl, by any of the followingprocesses: A) which comprises providing a methylphosphondiamide compoundof the structure ##STR123## wherein R⁹ is alkyl or arylalkyl, treatingthe above diamide with a metalating agent to form an anion of thediamide, alkylating the anion of the diamide by treating with a halideof the structure

    R.sup.1 X

where X is I, Cl, Br, tosylate, or CF₃ SO₃ --, to form the alkylatedcompound ##STR124## treating the above alkylated diamide with ametalating agent to form the metalated alkylated compound, subjectingthe metalated alkylated compound to sulfuration with tetramethylthiuramdisulfide, to form a mixture of isomers of the structures ##STR125##separating the isomers into the α-(S) isomer and α-(R) isomer, treatingthe desired isomer with an acid to form the desired diacid ##STR126##treating the diacid with an oxidizing agent and then with base to formthe desired enantiomer ##STR127## where M is an alkali metal; or B)forming an enantiomer of said phosphonosulfonate compound, whichcomprises providing a methylphosphondiamide of the structure ##STR128##wherein R⁹ is alkyl or arylalkyl, treating the above diamide with ametalating agent to form the corresponding anion salt, treating theanion salt with sulfur and a dialkylthiocarbamoyl halide to form adithiocarbamoylate of the structure ##STR129## treating thedithiocarbamoylate with a metalating agent to form the correspondingmetalated compound, treating the so-formed metalated compound with analkylating agent

    R.sup.1 X

to form a mixture of isomers of the structure ##STR130## separating theisomers, treating the desired isomer with an acid to form the desireddiacid ##STR131## treating the desired diacid with an oxidizing agentand then with base to form the desired enantiomer ##STR132## where M isan alkali metal; or C) forming an enantiomer of said phosphonosulfonatecompound, which comprises providing a phosphorous diamide of thestructure ##STR133## wherein R⁹ is alkyl, aryl or arylalkyl, treatingthe diamide with an aldehyde of the structure

    R.sup.1 --CHO

and a silylating compound to form a mixture of protected isomers of thestructures ##STR134## separating the isomers, reacting the desiredisomer with a fluoride source to form a deprotected compound of thestructure ##STR135## treating either deprotected isomer withdimethyldithiocarbamic acid, zinc salt and triphenylphosphine anddiisopropylazodicarboxylate (DIAD) to form the isomer ##STR136##treating the desired isomer with an acid to form the desired diacid##STR137## treating the desired diacid with an oxidizing agent and thenwith base to form the desired enantiomer ##STR138## where M is an alkalimetal; or D) forming an enantiomer of said phosphonosulfonate compound,which comprises providing a phosphorous diamide of the structure##STR139## wherein R⁹ is alkyl or arylalkyl, treating the diamide withan aldehyde of the structure

    R.sup.1 --CHO

and a base including a fluoride source to form a mixture of isomers ofdeprotected compound of the structures ##STR140## separating theisomers, treating either deprotected isomer with dimethyldithiocarbamicacid, zinc salt, triphenyl-phosphine and DIAD to form the isomer##STR141## treating the desired isomer with an acid to form the desireddiacid ##STR142## treating the desired diacid with an oxidizing agentand then with base to form the desired enantiomer ##STR143## where M isan alkali metal; or E) forming an enantiomer of said phosphonosulfonatecompound, which comprises providing an acid chloride of the structure##STR144## reacting the acid chloride with the metalated anion##STR145## (where R^(a) is alkyl or cycloalkyl) to form ##STR146##treating the product with (alkyl)₄ N.sup.⊕ I.sup.⊖ to form thecorresponding ammonium compound ##STR147## treating the abovedealkylated compound with a metalating agent and then with an alkylatingagent

    R.sup.1 X

to form the alkylated compound ##STR148## treating the desired isomerwith an acid and then with an ion exchange resin to form the desiredenantiomer ##STR149## where M is an alkali metal; or F) forming anenantiomer of said phosphonsulfonate compound, which comprises treatingan aldehyde of the structure

    R.sup.1 CHO

where R¹ is as defined in claim 1 with an (S,S)-diol ##STR150## in thepresence of an acid catalyst to form the acetal of the structure##STR151## treating the acetal with a trialkylphos-phite in the presenceof titanium tetrachloride to form the alcohol ##STR152## treating theabove alcohol with an oxidizing agent to form a compound of thestructure ##STR153## treating the above with p-toluenesulfonic acid inthe presence of dioxane to form the diester ##STR154## treating theabove diester with triphenyl phosphine, dimethyldithiocarbamic acid,zinc salt and diisopropyl azodicarboxylate to form ##STR155## treatingthe above diester with a bromotrimethylsilane to form the diacid##STR156## treating the diacid with an oxidizing agent and then with astrong base to form the desired enantiomer ##STR157## where M is analkali metal.
 2. The method as defined in claim 1 part A) or part E)wherein the final product is the (S)-enantiomer when Z is H ##STR158##and as defined in claim 1 part B) or part F) wherein the final productis the (R)-enantiomer when Z is H ##STR159##
 3. A method for forming anenantiomer of a phosphonosulfonate compound having the structure##STR160## wherein R² is OR⁵,R³ and R⁵ represent an alkali metal ion R⁴is an alkali metal ion; R¹ is a lipophilic group containing at least 7carbons; Z is H, halogen, lower alkyl or lower alkenyl, by any of thefollowing processes: A) which comprises providing amethylphosphondiamide compound of the structure ##STR161## wherein R⁹ isalkyl or arylalkyl, treating the above diamide with a metalating agentto form an anion of the diamide, alkylating the anion of the diamide bytreating with a halide of the structure

    R.sup.1 X

where X is I, Cl, Br, tosylate, or CF₃ SO₃ --, to form the alkylatedcompound ##STR162## treating the above alkylated diamide with ametalating agent to form the metalated alkylated compound, subjectingthe metalated alkylated compound to sulfuration with tetramethylthiuramdisulfide, to form a mixture of isomers of the structures ##STR163##separating the isomers into the α-(S) isomer and isomer, treating thedesired isomer with an acid to form the desired diacid ##STR164##treating the diacid with an oxidizing agent and then with base to formthe desired enantiomer ##STR165## where M is an alkali metal; or B)forming an enantiomer of said phosphonosulfonate compound, whichcomprises providing a methylphosphondiamide of the structure ##STR166##wherein R⁹ is alkyl or arylalkyl, treating the above diamide with ametalating agent to form the corresponding anion salt, treating theanion salt with sulfur and a dialkylthiocarbamoyl halide to form adithiocar-bamoylate of the structure ##STR167## treating thedithiocarbamoylate with a metalating agent to form the correspondingmetalated compound, treating the so-formed metalated compound with analkylating agent

    R.sup.1 X

to form a mixture of isomers of the structure ##STR168## separating theisomers, treating the desired isomer with an acid to form the desireddiacid ##STR169## treating the desired diacid with an oxidizing agentand then with base to form the desired enantiomer ##STR170## where M isan alkali metal; or C) forming an enantiomer of said phosphonosulfonatecompound, which comprises providing a phosphorous diamide of thestructure ##STR171## wherein R⁹ is alkyl, aryl or arylalkyl, treatingthe diamide with an aldehyde of the structure

    R.sup.1 --CHO

and a silylating compound to form a mixture of protected isomers of thestructures ##STR172## separating the isomers, reacting the desiredisomer with a fluoride source to form a deprotected compound of thestructure ##STR173## treating either deprotected isomer withdimethyldithiocarbamic acid, zinc salt and triphenylphosphine anddiisopropylazodicarboxylate (DIAD) to form the isomer ##STR174##treating the desired isomer with an acid to form the desired diacid##STR175## treating the desired diacid with an oxidizing agent and thenwith base to form the desired enantiomer ##STR176## where M is an alkalimetal; or D) forming an enantiomer of said phosphonosulfonate compound,which comprises providing a phosphorous diamide of the structure##STR177## wherein R⁹ is alkyl or arylalkyl, treating the diamide withan aldehyde of the structure

    R.sup.1 --CHO

and a base including a fluoride source to form a mixture of isomers ofdeprotected compound of the structures ##STR178## separating theisomers, treating either deprotected isomer with dimethyldithiocarbamicacid, zinc salt, triphenyl-phosphine and DIAD to form the isomer##STR179## treating the desired isomer with an acid to form the desireddiacid ##STR180## treating the desired diacid with an oxidizing agentand then with base to form the desired enantiomer ##STR181## where M isan alkali metal; or E) forming an enantiomer of said phosphonosulfonatecompound, which comprises providing an acid chloride of the structure##STR182## reacting the acid chloride with the metalated anion##STR183## (where R^(a) is alkyl or cycloalkyl) to form ##STR184##treating the above reaction product with (alkyl)₄ N.sup.⊕ I.sup.⊖ agentto form the corresponding ammonium compound ##STR185## treating theabove de alkylated compound with a metalating agent and then with analkylating agent

    R.sup.1 X

to form the alkylated compound ##STR186## treating the desired isomerwith an acid and then with an ion exchange resin to form the desiredenantiomer ##STR187## where M is an Alkali metal; or F) forming anenantiomer of said phosphonosulfonate compound, which comprises treatingan aldehyde of the structure

    R.sup.1 CHO

where R¹ is as defined in claim 1, with an (R,R)-diol ##STR188## in thepresence of an acid catalyst to form the acetal of the structure##STR189## treating the acetal with a trialkylphos-phite in the presenceof titanium tetrachloride to form the alcohol ##STR190## treating theabove alcohol with an oxidizing agent to form a compound of thestructure ##STR191## treating the above with p-toluenesulfonic acid inthe presence of dioxane to form the diester ##STR192## treating theabove diester with triphenyl phosphine, dimethyldithiocarbamic acid,zinc salt and diisopropyl azodicarboxylate to form ##STR193## treatingthe above diester with a bromotrimethylsilane to form the diacid##STR194## treating the diacid with an oxidizing agent and then with astrong base to form the desired enantiomer ##STR195## where m is aAlkali metal.
 4. The method as defined in claim 3 part A) or part E)wherein the final product is the (R)enantiomer when Z is H ##STR196## 5.The method as defined in claim 1 part B) or part F) wherein the finalproduct is the (S)-enantiomer when Z is H ##STR197##
 6. The method asdefined in claim 1 wherein R¹ is alkyl containing 7 to 25 carbons in thechain; alkenyl containing from 7 to 25 carbon atoms in the chain andfrom 1 to 6 double bonds; alkynyl containing 1 to 6 triple bonds; mixedalkenyl-alkynyl containing 1 to 5 double bonds and 1 to 5 triple bonds;or aryl; and where in the above groups alkenyl, alkynyl and/or aryl maybe substituted or unsubstituted; cycloheteroalkyl linked through acarbon on the ring or a heteroatom; cycloalkyl; heteroarylalkyl;cycloalkylalkyl; heteroaryl; cycloheteroalkylalkyl; alkyl; or a group ofthe structure ##STR198## wherein Ar is aryl or heteroaryl, and Ar mayinclude one to three additional rings fused to Ar, and wherein (CH₂)_(p)contains from 1 to 15 carbons in the chain and may include 0, 1, 2 or 3double bonds and/or 0, 1, 2 or 3 triple bonds in the normal chain, andmay contain an ether or amino function in the chain, and/or may include0, 1, 2 or 3 substituents as defined below for R⁶ ; and R⁶, R⁷, R⁸ andR^(8a) are the same or different and are H, alkyl containing 1 to 40carbons, alkoxy containing 1 to 40 carbons, alkenyl containing 2 to 40carbons, alkenyloxy containing 2 to 40 carbons, alkynyl containing 2 to40 carbons, alkynyloxy containing 2 to 40 carbons, hydroxy, halogen,nitro, amino, thiol, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxy,alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino,cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, cycloalkyl,cycloalkylalkyl, Ar-alkyl, ArO, Ar-amino, Ar, Ar-thio, Ar-sulfinyl,Ar-sulfonyl, cyano, Ar-carbonyloxy, or Ar-carbonylamino.
 7. The methodas defined in claim 3 wherein R¹ is alkyl containing 7 to 25 carbons inthe chain; alkenyl containing from 7 to 25 carbon atoms in the chain andfrom 1 to 6 double bonds; alkynyl containing 1 to 6 triple bonds; mixedalkenyl-alkynyl containing 1 to 5 double bonds and 1 to 5 triple bonds;or aryl; and where in the above groups alkenyl, alkynyl and/or aryl maybe substituted or unsubstituted; cycloheteroalkyl linked through acarbon on the ring or a heteroatom; cycloalkyl; heteroarylalkyl;cycloalkylalkyl; heteroaryl; cycloheteroalkylalkyl; or a group of thestructure ##STR199## wherein Ar is aryl or heteroaryl, and Ar mayinclude one to three additional rings fused to Ar, and wherein (CH₂)_(p)contains from 1 to 15 carbons in the chain and may include 0, 1, 2 or 3double bonds and/or 0, 1, 2 or 3 triple bonds in the normal chain, andmay contain an ether or amino function in the chain, and/or may include0, 1, 2 or 3 substituents as defined below for R⁶ ; and R⁶, R⁷, R⁸ andR^(8a) are the same or different and are H, alkyl containing 1 to 40carbons, alkoxy containing 1 to 40 carbons, alkenyl containing 2 to 40carbons, alkenyloxy containing 2 to 40 carbons, alkynyl containing 2 to40 carbons alkynyloxy containing 2 to 40 carbons, hydroxy, halogen,nitro, amino, thiol, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxy,alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino,cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, cycloalkyl,cycloalkylalkyl, Ar-alkyl, ArO, Ar-amino, Ar, Ar-thio, Ar-sulfinyl,Ar-sulfonyl, cyano, Ar-carbonyloxy, or Ar-carbonylamino.
 8. The methodas defined in claim 6 where in the final product R¹ is ##STR200##wherein n is 2, 3 or
 4. 9. The method as defined in claim 8 where in R¹,n is
 3. 10. The method as defined in claim 7 where in the final productR¹ is ##STR201## wherein n is 2, 3 or
 4. 11. The method as defined inclaim 10 where in R¹, n is 3.